Glioblastoma Multiforme: Pathogenesis and Treatment Constantinos Alifieris, Dimitrios T. Trafalis PII: DOI: Reference:
S0163-7258(15)00096-0 doi: 10.1016/j.pharmthera.2015.05.005 JPT 6780
To appear in:
Pharmacology and Therapeutics
Please cite this article as: Alifieris, C. & Trafalis, D.T., Glioblastoma Multiforme: Pathogenesis and Treatment, Pharmacology and Therapeutics (2015), doi: 10.1016/j.pharmthera.2015.05.005
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ACCEPTED MANUSCRIPT P&T # 22714 Glioblastoma Multiforme: Pathogenesis and Treatment Constantinos Alifieris, Dimitrios T. Trafalis
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Laboratory of Pharmacology, Medical School, University of Athens, Greece
Corresponding Author:
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Assis. Professor Dimitrios Trafalis, MD, PhD
Lab. Of Pharmacology, Medical School, University of Athens
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75 Mikras Asias Str., 11527-Goudi, Athens, Greece (Building 16, 1st floor) Tel.: +30 210 746 2587; Fax: +30 210 746 2504
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Email: [email protected]
ACCEPTED MANUSCRIPT Abstract Each year, about 5-6 cases out of 100,000 people are diagnosed with primary malignant brain tumors, of which about 80% are malignant gliomas (MGs). Glioblastoma multiforme (GBM)
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accounts for more than half of MG cases. They are associated with high morbidity and mortality. Despite current multimodality treatment efforts including maximal surgical resection if feasible,
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followed by a combination of radiotherapy and/or chemotherapy, the median survival is short: only
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about 15 months. A deeper understanding of the pathogenesis of these tumors has presented opportunities for newer therapies to evolve and an expectation of better control of this disease.
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Lately, efforts have been made to investigate tumor resistance, which results from complex alternate signaling pathways, the existence of glioma stem-cells, the influence of the blood-brain
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barrier as well as the expression of 06-methylguanine-DNA methyltransferase. In this paper, we review up-to-date information on MGs treatment including current approaches, novel drug-
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future treatment perspectives.
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delivering strategies, molecular targeted agents and immunomodulative treatments, and discuss
Keywords: glioblastoma, treatment, review, pharmacology, targeted therapy, stem cell
Abbreviations
AKT, Protein kinase B; BBB, blood-brain barrier; BCNU, carmustin; CCNU, lomustin; c-MET, hepatocyte growth factor receptor; EGF(R), Epidermal growth factor (receptor); EGFRvIII, epidermal growth
factor
receptor
variant
III;
ERK,
Extracellular
signal-regulated
kinases;
FTI,
Farnesyltransferase inhibitor; GBM, Glioblastoma multiforme ; Gli1, Glioma-associated oncogene-1; HDAC, Histone deacetylase 1; HER2, Human epidermal growth factor receptor 2; HGF, Hepatocyte growth factor ; Hsp, heat-shock protein; IDH1, NADP+-dependent isocitrate dehydrogenase; MAb, Monoclonal antibody; MAPK, Mitogen-activated protein kinases; MG, Malignant glioma; MGMT, O6-methylguanine-DNA methyltransferase ; miRNA, micro ribonucleic acid; MRI, Magnetic resonance imaging; MTKI, Multitargeted tyrosine kinase inhibitor ; mTOR, Mammalian target of 2
ACCEPTED MANUSCRIPT rapamycin ; OS, overall survival; PARP-1, poly(ADP-ribose)polymerase-1; PCV, procarbazine, lomustine and vincristine; PDGF(R), Platelet-derived growth factor (receptor); PFS, Progression-free survival; PFS-6, Six-month progression-free survival; PI3K, Phosphotidylinositol 3-kinase ; PTEN,
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phosphatase and tensin homolog; RAF, Rapidly accelerated fibrosarcoma; RAS, Rat sarcoma; RT, Radiotherapy; SHH, Sonic hedgehog; STAT3, Signal transducer and activator of transcription 3; TKI,
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Tyrosine kinase inhibitor; TMZ, Temozolomide; TTP, time-to-progression;
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endothelial growth factor (receptor);
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Table of contents
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1. Introduction 2. Pathogenesis 3. Treatment
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5. References
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4. Conclusion
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VEGF(R), Vascular
ACCEPTED MANUSCRIPT 1. Introduction Each year, about 5-6 cases out of 100,000 people are diagnosed with primary malignant brain tumors, of which about 80% are malignant gliomas (MGs) [Stupp et al., 2010 b;
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Schwartzbaum et al, 2006]. Gliomas, the most common group of primary brain tumours, include astrocytomas, oligodendrogliomas and ependymomas. According to World Health Organization
anaplastic
oligodendroglioma,
anaplastic
oligoastrocytoma
and
anaplastic
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astrocytoma,
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(WHO) malignant gliomas are subcategorized into grade III/IV tumors such as anaplastic
ependymomas, as well as grade IV/IV tumors, as glioblastoma multiforme (GBM). The WHO grade is
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assigned based on certain pathological features, such as nuclear atypia, mitotic activity, vascular
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proliferation, necrosis, proliferative potential and features clinical course and treatment outcome [Louis et al., 2007]. Its incidence in the United States is estimated around 3:100,000 while more than 10,000 cases are diagnosed annually. It constitutes 45.2% of all malignant central nervous
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system (CNS) tumors, 80% of all primary malignant CNS tumors and approximately 54.4% of all
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malignant gliomas. Mean age at diagnosis is 64 years and it is 1.5 times more common in men than
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women and 2 times more common in whites compared to blacks [Ostrom et al., 2013]. The incidence has increased slightly over the past 20 years mostly due to improved radiologic diagnosis and especially in elderly [Fisher et al., 2007]. In terms of treatment, grade III tumors and GBM are grouped together and treated similarly. Clinically, patients with GBM may present with headaches, focal neurologic deficits, confusion, memory loss, personality changes or with seizures. Diagnosis and treatment response is suggested by magnetic resonance imaging (MRI) and the use of adjunct technology such as functional MRI, diffusion-weighted imaging, diffusion tensor imaging, dynamic contrast-enhanced MRI, perfusion imaging, proton magnetic resonance spectroscopy and positron-emission tomography [Wen et al., 2008]. Etiologically, there are known linked risk factors that lead to development of GBM Environmental risk factors include primarily exposure to therapeutic ionizing radiation and factors such as vinyl chloride or pesticides, smoking, petroleum refining or production work and 4
ACCEPTED MANUSCRIPT employment in synthetic rubber manufacturing [Wrensch et al., 2002]. Additional factors such as exposure to residential electromagnetic fields, formaldehyde, diagnostic irradiation and cell phones have not been proven to lead to GBM. However, regarding cell phone irradiation, a metanalysis
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released in 2007 did show increased incidence among people who used cell phones for at least 10 years and especially those who had mostly unilateral exposure [Hardell et al., 2007].
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Currently, maximal surgical resection plus radiotherapy plus concomitant and adjuvant
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temozolomide or carmustin wafers (Gliadel) is the standard of care in patients younger than 70 years old with newly diagnosed GBM. However, recurrence seems to be the rule despite standard
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care. Lately, attention has been given to understand the initial molecular pathogenesis of these
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tumors including alterations in cellular signal transduction pathways, the occurrence of resistance to therapy and to find methods to penetrate easier the natural blood-brain barrier (BBB). Despite these efforts to treat however, it remains an incurable disease and the prognosis falls in a poor
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survival range of 12-15 months (median 14.6 months) and a mean survival rate of only 3.3% at 2
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years and 1.2% at 3 years [Scott et al., 1998; Stupp et al., 2005].
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Glioma stem cells contribute to resistance to standard radiotherapy via preferential activation of DNA-damage-response pathways; and to standard chemotherapy via O6methylguanine-DNA methyltransferase (MGMT), the inhibition of apoptosis and the up-regulation of multidrug resistance genes [Dean et al., 2005]. Thus, current efforts are directed towards personalized treatment and through blocking prime signaling pathways in gliomagenesis, surpassing acquired resistance and penetration of BBB. In this article we review the current concepts as well as emerging advances in the treatment of GBM with an emphasis on chemotherapy and targeted agents.
2. Pathogenesis The ongoing research on the pathogenesis of malignant gliomas has given opportunities for newer therapies to evolve as well as promises for better control of the disease. Efforts are given to understand the development of tumor resistance [Dean et al., 2005; Furnari et al., 2007]. 5
ACCEPTED MANUSCRIPT A small subgroup (about 5%) of patients with gliomas, is associated with certain hereditary syndromes [Farrell et al., 2007] (table 1). All other patients with gliomas represent sporadic cases. An important aspect of the pathogenesis of gliomas is that malignant transformation results from
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the sequential accumulation of genetic alterations and abnormal regulation of growth factor signaling pathways. Aberrant proliferations is thus mediated via molecules such as vascular
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endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor
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(PDGF) and hepatocyte growth factor (HGF) and loss of phosphotensin analogue (PTEN). Downstream cascades in the growth signaling pathways (including PI3K/AKT) may be triggered
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[Wen et al., 2008]. Also, when those tumors recur, they often show progression to a higher
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histologic grade and thus, acquire a different name; this actually is a representation of progression along a classification scheme, the natural course of the disease, rather than a new disease [Louis, 2006]. Among the alterations that are most frequently seen in low-grade astrocytomas are
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mutations affecting p53 and overexpression of platelet-derived growth factor α (PDGF-α) and its
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receptor. The transition to a higher grade is associated to disruption of RB, p16/CDKNαA and 19q
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tumor suppressor genes [Louis, 2006].
GBM Clinical subtypes: GBM, is usually described in two different clinical forms, primary and secondary GBM [Kleihues et al., 1999]. Primary GBM, is the most common form (about 95%) and arises typically de novo, within 3-6 months, in older patients. Secondary GBM arises from prior low-grade astrocytomas (over 10-15 years) in younger patients. While primary and secondary forms show some molecular differences, the end result is pretty much the same since the same pathways are affected and respond similarly to current standard treatment. Primary GBM often has amplified, mutated epidermal-growth factor receptor (EGFR) which encodes altered EGFR (known as EGFRvIII) whereas secondary GBM has increased signaling through PDGF-A receptor. Both types of mutations lead to increased tyrosine kinase receptor (TKR) activity and consequently to activation of RAS and PI3K pathways. Again, primary GBM have commonly amplification of MDM2 gene (encodes for an inhibitor of p53), PTEN mutations and homozygous deletions of CDKN2A whereas secondary GBM usually has more prevalent p53 mutations, IDH1 mutations, MET 6
ACCEPTED MANUSCRIPT amplification and overexpression of PDGFRA. Finally, progression of low-grade glioma to high-grade is associated with inactivation of the retinoblastoma gene (RB1) and increased activity of human double minute 2 (HDM2) [Louis, 2006; Kleihues et al., 1999]. These aberrations primarily lead to
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abnormal regulation of two major cellular systems –the growth factor mediated signaling pathways and the cell cycle- and play a role in the increased cell proliferation, inhibition of apoptosis, invasion
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and angiogenesis [Louis ., 2006].
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Mutation in the nicotinamide adenine dinucleotide phosphate (NADP+)-dependent isocitrate dehydrogenase (IDH1) is conferring favorable prognostic value and prediction of response
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to temozolomide in GBM. However, patients with wild type IDH1 anaplastic astrocytomas exhibit
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worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of gliomas [Hartmann et al., 2010]. IDH1 mutations were found in less than 5% of primary GBM and characteristically in greater than 80% of secondary GBM. A recent
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meta-analysis study associated IDH1 mutations in GBM with improved OS [Cheng H., et al., 2013].
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GBM Molecular subtypes: Based on the growing understanding of molecular heterogeneity
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in GBM, the Cancer Genome Atlas (TCGA) divided this tumor in molecular subclasses termed classical, mesenchymal, proneural and neural types based on genetic alterations and expression profiles especially of PDGFRA, EGFR, NF1 and IDH1. Classical GBM is defined by aberrant EGFR amplification, astrocytic cell expression pattern and loss of chromosome 10 whereas IDH1, TP53 or NF1 mutations are not common. The mesenchymal subtype is defined by NF1 and PTEN mutations, a mesenchymal expression profile and less EGFR amplification than in other GBM types. The proneural subtype is characterized by PDGFRA focal amplification, TP53 and IDH1 mutations with an oligodenrocytic cell expression profile and younger presentation age. Finally, the neural subtype, is
characterized
by
normal
brain
tissue
gene
expression
profile
as
well
as
astrocytic/oligodendrocytic cell markers [Verhaak et al., 2010]. Primary and secondary GBM may be indistinguishable histologically but apparently differ in genetic and epigenetic profiles. Most GBM tumors with IDH1 mutations have the proneural gene expression pattern but only 30% of preneural GBM has the IDH1 mutation. Thus, IDH1 mutation is a more reliable and definitive molecular 7
ACCEPTED MANUSCRIPT diagnostic criterion of secondary GBM compared to clinical criteria. Secondary GBM (almost always the proneural subtype) is genetically more homogenous group regarding IDH1 mutation as compared to primary GBM [Ohgaki et al., 2013]. This heterogeneity of GBM profiles leads to
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different treatment efficacy among patients indicating that therapy must be personalized to target each patient’s alterations in the molecular level.
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Stem cells: The need for better understanding and managing patients with GBM, has led to
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the search for a defined cell type to target on. The discovery of multi-potent neural stem cells within the CNS which are capable of proliferation, self-renewal and differentiation, has led to the
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suggestion that a specific transformed CNS cell exists, which has the respective biological attributes
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of a somatic stem cell and may behave as a tumor initiating cell (TIC) [Facchino et al., 2011]. These stem cells express surface cluster designation markers such as CD133. Extensive studies, have led to the conclusion that those glioma stem cells promote angiogenesis by producing VEGF and can
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differentiate into pericytes, thus they create an optimal microenvironment for survival [Cheng L., et
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al., 2013].
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Mutations leading in gliomagenesis can occur in neural stem cells [Koso et al., 2012]. Possibly neural stem cells pass on mutations to downstream cells such as oligodendrocyte precursor cells (OPC), which are putative glioma cells. Introducing Neurofibromin-1 and p53 mutations into OPCs produces gliomagenesis in vitro (as occurs in Li-Fraumeni and Neurofibromatosis-1) [Liu et al., 2011]. Sonic hedgehog (SHH) signaling pathway, is presumed to be involved in the resistance (both chemotherapy and radiotherapy) and self renewal of cancer stem cells. Glioma-associated oncogene-1 (Gli1) –originally thought of being an oncogene involved in the pathogenesis of GBM- is part of SHH pathway. Normally, SHH acts via activation of the Gli1 transcription factor and thus participates in maintenance and proliferation of neural stem cells [Clement et al., 2007]. Cancer stem cells can be useful as targets by means of immunotherapy or inhibition of important specific pathways, as with signal transducer and activator of transcription 3 (STAT 3) or the activator bone marrow x-linked kinase (BMX) [Nduom et al., 2012]. 8
ACCEPTED MANUSCRIPT Targeting of stem cell signaling pathways is an evolving field which already shows some promising results. Innovative therapeutic responses as well as preventive approaches may be directed by this type of cells. Molecular GBM phenotype has broadened the list of targets in
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tumorgenic pathways. In GBM several tumor suppressor and oncogenic genes seem to be modulated by miRNAs thus delivery of genes or microRNAs (miRNA) can be another form of
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treatment [Møller et al., 2013].
3. Treatment
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Currently, the standard approach in managing GBM includes consideration of maximum
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surgical resection -considering that the entire tumor cannot be removed because GBM infiltrates surrounding tissue- radiation therapy (RT) and medical management/chemotherapy. It also includes symptomatic treatment of seizures, cerebral edema, infections, depression, cognitive
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dysfunction, fatigue and venous thromboembolism [Wen et al., 2006 a]. However, the analysis of
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symptom palliation is not in the scope of this review.
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The best therapeutic target is to pursuit a more individualized perspective. Thus, treatment depends on several factors such as the time of diagnosis, new onset or recurrence, the performance status and the age of the patient. Most GBM patients will follow a standard treatment after surgical resection consisting of external beam irradiation five times a week for six weeks, as well as oral temozolomide daily. Most patients will recur within 6.9 months of initial diagnosis. New agents or treatment administration techniques are typically initially tested first in the recurrent setting where there are some approved treatment alternatives. Table 2 depicts a summary of the current standard options for treatment of newly diagnosed GBM. In patients with either clinical or radiological progression, various treatment approaches have been assessed. As part of the multidisciplinary management of high grade gliomas, options include further surgery in selected patients, re-irradiation if also eligible, systemic chemotherapy, and clinical trial participation [Wen et al., 2008; Butowski et al., 2006]. As most patients are ineligible for re-operation or re-irradiation, clinical trial participation is the best option. Chemotherapy options (given as single agents) for high9
ACCEPTED MANUSCRIPT grade gliomas include carboplatin, irinotecan, carmustine (BCNU), etoposide and procarbazine, lomustine and vincristine (PCV) combination. Exciting preliminary data from clinical phase I/II trials support the development of epidermal growth factor receptor (EGFR) antagonists, mammalian
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target of rapamycin (mTOR) inhibitors, antiangioogenesis agents and other targeted inhibitors [Villano et al., 2009]. Even further, investigational approaches using convection enhanced delivery,
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stem cell treatment, immunotherapy and gene therapy based on recent pathogenetical discoveries,
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give excitement and promise for the future.
Chemotherapy for glioblastoma multiforme: Cytotoxic therapy for GBM has evolved, more
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due to the approval of temozolomide -an alkylating agent- for newly diagnosed GBM. Active agents
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include also the nitrosureas: carmustine (BCNU) and lomustine (CCNU), platinum agents, etoposide, irinotecan and PCV combination.
Temozolomide (TMZ) is a newer oral alkylating agent that has excellent penetration into
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the central nervous system. It is an imidazotetrazine derivative of dacarbazine. It has 100%
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bioavailability and promotes the methylation of the O6 position on guanine (N7-guanine and N3
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adenine). It was approved in 1999 for usage against malignant gliomas. Major toxicities include nausea and myelosuppression (often low platelet counts). Usually, an oral 5-HT3 antagonist is given 30-60 minutes prior to each dose. Dosage is usually started at 75mg/m2 daily concurrently with 6 weeks of regional radiotherapy to the surgical cavity and followed by 6 adjuvant cycles with maintenance dose at 150mg/m2 daily p.o. for 5 days for the first cycle and if well tolerated then scaled up to 200mg/m2/d for 5 days in 28-day cycles [Villano et al., 2009; Chinot et al., 2001]. Concurrent RT and TMZ results in a median overall survival (OS) of 14.6 months and 2-year survival rate of 26.5%. Temozolomide can be effective for recurrent GBM while its efficacy can be increased with metronomic rather than standard schedule as well as with high average daily dose (>100mg/m2) [Chen et al., 2013]. Patients with promoter MGMT methylation treated with RT/TMZ have a median survival of 23 months and 5- year OSof 14% versus RT alone (15 months and 5% respectively) [Stupp et al., 2009].
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ACCEPTED MANUSCRIPT The nitrosureas, carmustine (1,2 bis[2-chloreoethyl]-1-nitrosurea BCNU) and lomustine (CCNU), are two alkylating drugs used in the treatment of GBM and are associated with nausea, vomiting, rash, pulmonary fibrosis (rare) and a delayed myelosuppression and typically given in the
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dosage of 80mg/m2/d i.v. on days 1-3 every 6-8 weeks with radiation [Green et al., 1983]. Single agent BCNU is used most often as second line treatment in GBM that has progressed after TMZ.
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Carmustine biodegradable wafers (Gliadel) are an implantable depot form of BCNU that are placed
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in the cavity that is formed after resection of newly diagnosed or recurrent tumor. The wafers release topically BCNU for about 3 weeks. Although they are considered relatively safe they are not
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used by most centers because of delayed wound healing, intracranial edema, cerebrospinal fluid
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leakage, intracranial infection and seizures have been reported. Also, alterations in blood-brainbarrier make the interpretation of MRI unreliable [Nagpal et al., 2012]. Irinotecan, etoposide and cisplatin have been used in the treatment of GBM demonstrating
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modest efficacy as adjuvant chemotherapy. Since the approval of TMZ, they are mostly used as
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treatment after progression or recurrence. Since bavacizumab (see below), is increasingly being
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used in the recurrent setting, combinations of platinum compounds with bevacizumab have been used [Carrillo et al., 2012].
The PCV regimen combining procarbazine, lomustine (CCNU) and vincristine is commonly used in the treatment of anaplastic astrocytomas and oligodendrogliomas. Procarbazine is also a monoamine oxidase inhibitor and is associated with allergies and hypertensive crisis especially in response to certain foods such as those containing tyramine –aged cheese, nuts, red wine- which patients are advised to avoid consuming. Vincristine is a vinca alkaloid (binds to tubulin), is associated with a syndrome of jaw pain after the first dose and maybe peripheral neuropathy. This combination is usually given as CCNU 110mg/m2 p.o. on day 1, procarbazine 60 mg/m2/d p.o. on days 8-21 and vincristine 1.4 mg/m2 (maximum dose 2 mg) i.v. on days 8 and 29, repeated every 6 weeks [Glass et al., 1992]. PCV in recurrent GBM has not shown significant results [Schmidt et al., 2006].
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ACCEPTED MANUSCRIPT Investigational cytotoxic agents: GRN1005 (ANG1005) is a novel agent that consists of three paclitaxel molecules linked to a novel peptide –angiopep- that allows it to be transported across the blood-brain barrier through the low-density lipoprotein-related protein 1 receptor. In a phase I
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study, prodrug GRN1005 was tried in patients with recurrent or progressive malignant gliomas and it was fairly well tolerated while showed antitumor activity. It penetrated the blood-brain barrier
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[Drappatz et al., 2013]. Dichloroacetate (DCA) is an inhibitor of the mitochondrial pyruvate
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dehydrogenase kinase induces apoptosis in vitro and in vivo of GBM cell lines [Michelakis et al., 2012]. A phase II study evaluates DCA in patients with GBM and results are pending
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(NCT00540176). RTA 744 is a close chemical analogue of doxorubicin but is more effective in
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crossing the blood brain barrier and is able to achieve high concentrations in the CNS tumor tissue in animal models. A phase I study of RTA 744 in patients with recurrent high-grade gliomas has been completed but results have not been published yet (NCT00526812).
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Resistance to chemotherapy and radiotherapy: Many GBMs have intrinsic or acquired
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resistance to chemotherapy. MGMT gene promoter methylation and thus silencing and
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downregulation of the gene is an important mechanism of resistance to temozolomide treatment in GBM. MGMT is a repair gene that removes alkyl groups from the O6 position of guanine and in this way it alleviates the effects of alkylating drugs (temozolomide or the nitrosureas) [Hegi et al., 2005; Esteller et al., 2000]. Methylation of MGMT is found in 30-60% of GBM cases and is associated with a favorable outcome if treated with alkylating agents [Hegi et al., 2005]. A common mechanism that confers this resistance is mediated by MGMT. If the promoter of this gene is methylated, glioma cells are more sensitive to temozolomide. One way of surpassing this resistance is with dose-dense (days 1-21 every 28 days) or dose-intense regimens [Clarke et al., 2009], or by direct inhibition of MGMT via O6-benzylguanine in combination with TMZ [Quinn et al., 2009]. A second mechanism that gives resistant properties to these tumors is that of poly(ADP-ribose)polymerase-1 (PARP-1). PARP-1 is a critical base-excision-repair gene and that when disrupted results in persistence of potentially lethal N7- and N3- purine lesions contributing to TMZ cytotoxicity especially when O6methylguanine adducts are repaired or tolerated. PARP-1 small molecule inhibitors such as BSI-201 12
ACCEPTED MANUSCRIPT (iniparib) and ABT-888 are promising either alone or in combination with TMZ [Wen et al., 2008, Zhang et al., 2012]. In preclinical trials, inhibition of another target important to base-excisionrepair, abasic (AP) endonocluease-1 (APE-1) shows potentiation of TMZ activity [Zhang et al., 2012].
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There is evidence that glioma stem cells contribute to GBM chemoresistance. Stem cells from highly chemotherapy resistant grade IV gliomas show expression of multidrug resistance
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protein-1 (MRP1) transporters and grade II gliomas show expression of P-glycoprotein (Pgp) [De
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faria et al., 2008]. Moreover, cancer stem cells express MDR1 at higher levels than differentiated cancer cells, favoring resistance to chemotherapy agents such as temozolomide, etoposide,
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paclitaxel and carboplatin in undifferentiated cells and thus serving as an adequate reasoning for
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this high frequency of tumor recurrence with existing treatment [Liu et al., 2005]. TMZ also results in induction of EGFRvIII and EGFR expansion, which can be blunted by the use of EGFR inhibitors such as erlotinib [Munoz et al., 2014]. Medication such as verapamil and cyclosporine A that inhibit
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[Linnet et al., 2008].
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p-glycoprotein in vitro, can increase brain retention of chemotherapy drugs such as vincristine
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Drug molecular targets in glioblastoma multiforme: The continuously evolving field of understanding the molecular pathogenesis of GBM prompted to a more rational use of targeted molecular therapies. Inhibitors that target receptor tyrosine kinases (EGF, PDGF, VEGF, HGF, IGF receptors) and signal transduction inhibitors targeting mTOR, AKT/PI3K and farnesyltransferase are being investigated. Unfortunatelly, up till now, monotherapy with these agents show disappointing results or at most mild-modest efficacy with response that is between 0 to 15% and are unable to prolong the progression free survival [Sathornsumetee et al., 2007]. Because highly targeted agents were not being successful, the current approach is combined inhibition of multiple molecular targets within the same pathway (proximal and distal) or between separate-parallel pathways but with the cost of increased toxicity. Nevertheless, no combination therapy has shown enhanced clinical benefit over single agents [Wilson et al., 2014] Tyrosine kinase associated receptors serve in the transmission of signals from extracellular ligands to cell nucleus and share some common pathway mechanisms and intracellular signaling. 13
ACCEPTED MANUSCRIPT They are composed of a ligand-binding extracellular domain, a lipophilic transmembrane domain and an intracellular domain containing a catalytic site. In the absence of their associated ligand, tyrosine kinase receptors remain unphosphorylated, monomeric and inactive. After the appropriate
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ligand binds its associated receptor, the receptors undergo dimerization and then autophosphorylation in which the kinase domain of one receptor phosphorylates one or more
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intracellular tyrosine residues on the second receptor. Those phosphotyrosine residues in turn,
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become binding sites and recruit adaptor proteins and activate downstream effect on molecules which initiate specific signaling cascades with end result the regulation of gene transcription.
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Adaptor proteins include growth factor receptor-bound-2/son-of-sevenless (Grb2)/(SOS) effect on
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serine/threonine kinases such as RAS, phosphatidyloinositide-3-kinase (PI3K) and phospholipase C (PLC). Negative kinase regulators include PTEN in the PI3K pathway. Important intracellular mediators in oncogenic biochemical pathways include RAF-MEK-ERK, AKT and mTOR.
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The alterations in gene synthesis result in cell growth, proliferation, migration, angiogenesis
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and apoptosis. Within tumor cells, dysregulation can occur with various mechanisms mainly with
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overexpression or mutations of receptors and intracellular domains, activation of biomolecules, inactivating mutations of their negative regulators and lead to constitutive activation of signaling pathways and uncontrolled cellular survival, proliferation and invasion [Arora et al., 2005]. C-Kit is another receptor tyrosine kinase that acts similarly to EGFR and PDGFR and is found to be overexpressed in GBM. Binding of ligands and specifically the stem cell factor to c-Kit, results in receptor dimerization and activation of several transduction pathways including Akt, Src family kinases, PI3K, Ras/MAPK and PLC-γ. [Arora et al., 2005]. Angiogenic pathway inhibition: GBM is a highly vascularized malignancy with marked angiogenesis and high expression of VEGF which is also needed for stem cells to create an optimal functional environment. Antiangiogenic agents, a group of continuously evolving targeted therapeutics, have demonstrated promising results in many trials [Onishi et al., 2013]. Older agents like thalidomide and newer anti-VEGF or anti-VEGFR therapies, as well as anti-HGF and anti-avβ5 integrin molecules are included. VEGF is a member of the platelet-derived growth factor family. 14
ACCEPTED MANUSCRIPT There are numerous ligands for VEGF receptors (VEGFRs) including VEGF-A to –E and placenta growth factor. VEGFRs are expressed on vascular endothelial cells [Ferrara., 2005]. Ligand binding to VEGFR-1 (Fms-like tyrosine kinase 1 or Flt-1) induces endothelial cell migration, where as binding
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to VEGFR-2 (kinase insert domain-containing receptor or KDR) stimulates endothelial cell proliferation, increases vascular permeability (this probably accounts for the vasogenic edema of
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GBM seen on MRIs), increases the expression of proangiogenic factors (matrix metalloproteinase-1,
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urokinase-type plasminogen activator and it’s receptor, plasminogen activator inhibitor-1), has antiapoptotic effects and VEGFR-2 activates primarily the tyrosine kinase domains once ligands
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attach. Binding to VEGFR-3 (Flt-4) leads to lymphangiogenesis. Several factors may upregulate VEGF
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expression including hypoxia (the most important factor in tumor cells), HGF, PDGF, FGF, EGF, TNF, TGF-β, IL-1, c-KIT, the PI3K-Akt and Ras-MAPK pathways, acidosis, wound healing, endometriosis and embryogenesis [Ferrara., 2005]. Neoplasms such as GBM, require their own vascular supply to
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maintain survival beyond the size of 2 mm. The early small tumor extensions can receive the
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needed vascular supply from the glial vasculature by “co-opting” along the capillaries. To achieve
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this, angiogenesis must take place [Jain et al., 2007]. However, blocking the VEGF pathway provides means of blocking the new vessels with high permeability (“leaky vessels”) and thus decreasing hypoxia in the tumor and consequently they disrupt a vital mechanism of survival in glioma stem cells, they decrease neoangiogenesis, hypoxia, vascular permeability (and vasogenic edema) and increase chemotherapy delivery and radiosensitivity [Jain et al., 2007; Bao et al., 2006]. Inhibitors of VEGF signaling pathway include small molecule tyrosine inhibitors, MAbs and VEGF binding agents. EGFR is the most frequent amplified gene seen in malignant gliomas. The EGFR is one of four tyrosine kinase receptors within the ErbB receptor family, that is ErbB1 (EGFR/HER1), ErbB2 (HER2/neu), ErbB3 (HER3) and ErbB4 (HER4). Activation of these receptors result in turn in activation of multiple downstream signaling pathways as fore-mentioned, including the Ras/Raf/MEK/ERK1/2-mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3’-kinase(PI3K)/Akt/mTOR pathway and the signal transducer and activator of transcription 15
ACCEPTED MANUSCRIPT pathways (STAT 3 and 5). Ligands for these receptors include EGF and transforming growth factor α (TGF-α). These pathways affect cell proliferation, migration, differentiation, inhibition of apoptosis and upreguletion of VEGF expression and thus increased angiogenesis [Mendelsohn et al., 2006].
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Activation of EGFR can be due to: a) increased expression or activity of EGFR ligands or cofactors, b) EGFR gene amplification or increase in translation (50-60% of GBM cases), and c) activating
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mutations of EGFR, like the EGFRvIII mutant (mediates radioresistance and it confers a more
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malignant potential than the wild type receptor, found in 50-60% of GBMs) [Ye et al., 2012]. EGFR signaling alterations are associated with worse clinical prognosis, decreased OS and gliomagenesis
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[Shinojima et al., 2003]. Currently, EGFR inhibition has been tried by using small molecule tyrosine
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kinase inhibitors, monoclonal antibodies, peptide vaccines, antisense oligonucleotides and immunotoxin conjugates.
Platelet-derived growth factor (PDGF) and its receptor (PDGFR) are also commonly
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overactive in about 30% of GBM cases. The PDGF family consists of four members, PDGF-A through
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–D which signal through the alpha and beta PDGFR (PDGFR-α; PDGFR-β). Activation of PDGFR
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triggers multiple intracellular signaling pathways, much like the EGFR. They include PI3K, MAPK, Jak family kinase, Src family kinase and phospholipace C-gamma (PLC-γ) [Joensuu et al., 2005]. Thus, it promotes tumor growth through autocrine stimulation, angiogenesis through paracrine effects on reciprocal endothelial cells and affects tumor fibroblast regulation (which in turn leads to transvascular transport of drugs through alterations in intratumoral pressures) [Ostman et al., 2004]. PDGF expression (but not PDGFR-α) is associated with the tumor grade and proliferative activity of oligodendrogliomas [Majumdar et al., 2009]. PDGF-C has been shown to induce the maturation of blood vessels in GBM experimental models and attenuate the response to anti-VEGF treatment [di Tomaso et al., 2009]. Drugs that block the PDGFR include tyrosine kinase inhibitors and MAbs. Hepatocyte growth factor (HGF) or scatter factor activates the EGF, VEGF and HGF pathways. When it binds to the c-MET receptor, it activates intracellular signaling cascades similar to those triggered by the EGF and PDGF receptors such as MAPK, PI3K-Akt, V-Src and STAT. C-Met 16
ACCEPTED MANUSCRIPT signaling has been associated with gliomagenesis, increased cell growth, scattering and motility, invasion, resistance to apoptosis and angiogenesis [Sierra et al., 2011]. It has also been postulated that c-MET activation may bypass EGFR tyrosine kinase inhibition in sensitive cells by either
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autophosphorylation of c-MET or transphosphorylation of other ErbB receptors (‘cross talk’) thus acting as a mechanism of resistance to anti-EGFR treatment [Sierra et al., 2011]. HGF autocrine
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GBM may predict sensitivity of GBM cells to c-MET inhibitors and serum HGF levels may be serve as
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biomarker for the presence of autocrine tumors and responsiveness to c-Met inhibition therapy [Xie et al., 2012]. Also, targeting of the c-Met pathway is found to potentiate GBM rensposiveness
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to gamma irradiation [Lal et al., 2005]. Preclinical evidence have demonstrated that PTEN loss
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amplifies c-Met induced GBM malignancy and it is suggested that trials of the combination of antiHGF blocking plus PTEN restoration or mTOR inhibition should be carried out [Li et al., 2009]. Elevated serum HGF may be associated with poor response and a shorter PFS in patients with GBM
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undergoing first-line RT [Liang et al., 2014].
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Most important intacellular effector molecules in the pathogenesis of malignant gliomas
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are biochemically active serine/threonine kinases. These include PI3K, RAS, PLC etc. and either activation of them or inactivation of their negative regulators lead to excessive phosphorylation in the intracellular signal pathways and thus contribute to malignancy. RAS-RAF-MEK-MAPK pathway: The Ras gene superfamily encodes small GTP (guanine triphosphate)-binding proteins (GBPs) which are found in the inner cell membrane and regulate cellular functions, including cytoskeletal organization, protein trafficking, cellular differentiation and proliferation as well as secretion of angiogenetic molecules. Ras mutations are not common in malignant gliomas but they rather show increased Ras activity due to amplification or mutation of upstream growth factor receptors [Knobbe et al., 2004]. When Ras is triggered by either EGFR or PDGFR activation or through independent pathway alterations, the mitogenic signal through the mitogen activated protein kinase (MAPK also known as ERK) and phosphatidylinositol 3-kinase (PI3K) pathways are initiated. However, translocation of Ras to the cell membrane for activation requires a post-translational alteration which is catalyzed by farnesyltransferase. Farnesylation is 17
ACCEPTED MANUSCRIPT the rate-limiting step in RAS maturation although not unique for Ras [Sebti et al., 2004]. Downstream of Ras, is the pathway Raf-Mek-MAPK pathway. Activation of MAPK is associated with poor outcome in GBM [Pelloski et al., 2006].
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Phosphotidylinositol 3-kinase (PI3K) /AKT/mTOR (mammalian target of rapamycin) pathway is a group of serine/threonine kinases. PI3K can be activated by other tyrosine kinase receptors
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(EGFR, PDGFR, c-Met), active Ras or integrins. It regulates cellular mechanisms and when altered
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can lead to decrease of apoptosis, increase in cell growth and cell proliferation. It is a poor prognostic factor in patients with malignant gliomas [Chakravanti et al., 2004]. AKT (also known as
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protein kinase B), is a downstream effector of PI3K -activated when phosphorylated- and leads to
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the same cellular results. mTOR is downstreamed from AKT and can be activated by RAS pathway also. At least 2 separate mTOR complexes exist. Each complex is composed of a common regulatory subunit, the target of rapamycin (TOR) and a downstream-substrate-defining subunit. The latter
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includes raptor subunit (in mTOR-complex-1, mTORC1) and rictor subunit (in mTOR-complex-2,
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mTORC2). Rapamycin only inhibits mTORC1. The raptor subunit of mTORC1 regulates protein
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transcription which involves 4E-BP1 (initiation factor 43 binding protein-1) and p70s6K (ribosomal S6 kinase). The most important negative regulator of the PI3K/Akt/mTOR pathway seems to be PTEN (phosphate and tensin homologue) [Sheppard et al., 2012]. In GBM the PI3K/AKT/mTOR pathway is active in about 70% of cases and it seems to regulate the proliferation and tumorigenic potential in GBM cancer stem cells. Rapamycin seems to inhibit this potential in vitro but not in vivo, hence it may be of limited value as monotherapy in GBM [Mendiburu-Eliçabe et al., 2013]. Protein kinase C (PKC) is another serine/threonine kinase that regulates glioma cell proliferation, angiogenesis and invasion. It is activated by other tyrosine kinase receptors and Gprotein coupled receptors. PKC-β mediates VEGFR2 signalling through its associated MEK/MAPK pathway [Kreisl et al., 2010]. Apart from conferring resistance to chemo- and radio-therapy and increase in survival of stem cells the Sonic hedgehog/Gli1 (SHH/Gli1) pathway seems to also act in migration and glioma cell invasion [Wang et al., 2010]. 18
ACCEPTED MANUSCRIPT GBM is characterized by the presence of increased growth factor signaling, hypoxia, angiogenesis and the presence of brain glioma cancer-stem-cells, conditions in which Notch signaling could prove to be a key. Specifically, regarding stem-cells there is evidence that by
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blocking this pathway in combination with other targeted treatments, a better control of these neoplasms could be achieved [Stockhausen et al., 2012]. Gamma secretases, mostly known for their
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role in the final step of processing amyloid precursor protein in Alzheimer’s disease through the
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generation of amyloid-beta peptides, also play a key role in Notch signaling pathway[Stockhausen et al., 2012; Lin et al., 2010].
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The integrins are heterodimeric transmembrane cell adhesion molecules and receptors that
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bind multiple extracellular ligands (e.g. matrix proteins like collagen, laminins, vitronectins and fibronectins). This binding activates integrins and thus regulates tumor cell invasion and metastasis, migration, proliferation, angiogenesis and survival. The regulation of these effects is mediated via
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downstream signaling pathways that signal in parallel to other pathways like EGFR, VEGF and
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PDGFR. There are at least 24 integrin types and are widely expressed throughout the vasculature.
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The integrins alphaVbeta3 (αVβ3) and alphaVbeta5 (αVβ5) are highly expressed in malignant glioma tumor cells and on endothelial cells at tumor peripheral vessels. Peptide-based integrin inhibitors as well as monoclonal antibodies are being investigated as means of inhibiting this cellular mechanism. Integrin inhibitors decrease tumor hypoxia [Tabatabai et al., 2010]. Integrin overexpression has been found in glioma stem cell microenvironment [Lathia et al., 2010]. Molecular pathway & kinase inhibitors: EGFR tyrosine kinase inhibitors (TKIs) are small molecules that bind to the ATP-binding site on the tyrosine kinase domain of the receptor and inhibit the catalytic activity of the kinase. They can also inhibit fusion tyrosine kinases by blocking their dimerization. Furthermore, they interact with VEGFR and other human epidermal receptors [Yarden et al., 2001]. Examples include the competitive antagonists, erlotinib and gefitinib (administered orally), as well as the newer irreversible antagonists afatinib and dacomitinib. Erlotinib in two separate phase II trials with patients with recurrent GBM, showed that it is ineffective as monotherapy showing progression free survival at 6 months (PFS-6) in 3% of patients 19
ACCEPTED MANUSCRIPT and a median PFS of 2 months [Raizer et al., 2012] and PFS-6 in 11.4% vs 24% of control (treated with TMZ or carmustine) [van den Bent et al., 2009]. Gefitinib, in a phase II study with recurrent GBM patients, demonstrated event-free survival (EFS) of 13.2% at 6 months [Rich et al., 2004].
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Systemic toxicity has been used as a way to predict the clinical efficacy of treatment (e.g, rash, diarrhea). For example in a study, diarrhea from gefitinib treatment was associated with better
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OSwhereas EGFR expression (either EGFRvIII or wild-type) did not correlate with prediction of OS
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[Rich et al., 2005]. On the other hand, co-expression of EGFRvIII and PTEN in GBM seems to predict a better response to EGFR inhibition (fifty times more likely) [Mellinhoff et al., 2005]. In a phase II
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trial with patients with recurrent GBM given afatinib alone, showed PFS-6 in 3% of patients but
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possibly was more effective in patients with EGFRvIII mutations [Eisenstat et al., 2011]. A study of afatinib and radiotherapy with or without temozolomide is under way (NCT00977431). Dacomitinib (PF-299804) is a new pan-HER irreversible inhibitor that shows enhanced action against glioma-
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specific domain IV EGFR cysteine mutations [Greenall et al., 2014] and is currently been evaluated
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in two phase II studies, one with GBM patients with EGFR amplification or EGFRvIII expression
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(NCT01520870) and another in seeking of efficacy in recurrent/relapsed GBM (NCT01112527). As a conclusion, erlotinib appears to be more effective against malignant gliomas than gefitinib. Higher levels of EGFR expression can be associated with better response to erlotinib [Haas-Kogan, et al., 2005 a]. Although, EGFR has clearly a great and important role in the pathogenesis of high grade gliomas, trials up to date with EGFR inhibitors failed to show promising results. Explanations may be the acquisition of new resistance mutations and/or inability to cross effectively the blood brain barrier (BBB). Also, proximal block of the EGFR pathway, may be overridden by overactive distal effectors (high pAKT) [Haas-Kogan, et al., 2005 b]. Tyrosine kinase inhibitors have been developed to block the VEGF pathway. However, although they are many and primarily antagonize angiogenesis they also have mixed tyrosine kinase blocking effects. Inhibitors that have primarily VEGFR blocking effects include vatalanib, vandetanib, sunitinib, pazopanib, cediranib and cabozantinibe. They will be discussed below.
20
ACCEPTED MANUSCRIPT As in VEGFR pathway, small molecule inhibitors have been developed against PDGFR. However, they have mixed effects and are not selective for PDGFR. Examples of inhibitors with primarily actions against PDGFR include imatinib, dasatinib, nilotinib and tandutinib. They will be
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discussed below. Crenolanib (CP-868,596), a novel oral selective and potent PDGFR inhibitor, is currently being evaluated in a phase II study of adult malignant gliomas (NCT01229644) and in a
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phase I study of pediatric/young adult recurrent high grade gliomas (NCT01393912).
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Small molecule inhibitors targeting c-MET pathway have been developed but not all of them show selectivity for the c-MET receptor. SGX523 is a highly selective oral c-MET inhibitor that
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has been shown to be effective in vitro and in vivo against GBM cell lines. Although two separate
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phase I studies with SGX523 were prematurely terminated (NCT00606879, NCT00607399), it may still serve as a guide of investigating the role of MET in cancer until further clinical evaluation [Buchanan et al., 2009; Guessous et al., 2010].
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Farnesyltransferase inhibitors (FTIs) have been tried in the treatment of malignant gliomas.
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Tipifarnib (R115777), in a phase II trial exhibited modest efficacy as monotherapy in patients with
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recurrent malignant gliomas. PFS-6 was 11.9% for GBM patients. Toxicity was tolerated well except the subset of patients that received enzyme inducing antiepileptic drugs which presented an increased hematological toxicity [Cloughesy et al., 2006]. R115777 administered before RT in patients with newly diagnosed GBM and residual enhancing disease did not lead to any measurable benefit [Lustig et al., 2008; Nghiempu et al., 2011]. The R115777 plus RT combination with or without TMZ, in newly diagnosed GBM seems to be well tolerated [Nghiempu et al., 2011]. Another phase I/II trial of R115777 with RT in patients with newly diagnosed GBM produced a median OSof 60.4 weeks but time to progression (TTP) was only 18.1 weeks where both FGFR1 and αvβ3 integrin expressions being independent bad prognostic factors [Ducassou et al., 2013]. A phase I/II trial of the combination of sorafenib combined with erlotinib, tipifanib or temsirolimus in recurrent GBM has been completed and results are pending (NCT00335764). Lonafarnib (SCH66336) against U87 GBM cell lines improved activity of TMZ/RT [Chaponis et al., 2011]. In a phase I study on Ionafarnib with TMZ in malignant glioma patients demonstrated dose limiting hepatic, gastrointestinal 21
ACCEPTED MANUSCRIPT (vomiting, diarrhea, anorexia), renal, thrombotic and constitutional toxicities (headaches) [Desjardins et al., 2011]. In progressing GBM, intensifying TMZ treatment and adding lonafarnib a PFS-6 of 33% and partial response of 27% in previously non-responding patients was achieved
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[Gilbert et al., 2006]. In another phase I/Ib study of lonafarnib and dose-dense schedule of TMZ in recurrent/TMZ refractory GBM, toxicity was acceptable and PFS-6 was 38% and median survival
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13.7 months [Yust-Katz et al., 2013]. Manumycin, a FTI, has been found to induce reactive osxygen
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species (ROS) and glioma cell apoptosis, inhibits STAT3 and telomerase activity [Dixit et al., 2009] as wall as targets the IL1β-Ras-HIF-1α axis [Sharma et al., 2012].
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TLN-4601, a novel Ras-MAPK inhibitor, has been studied on first progression status of GBM
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in a phase II study. Although it was well tolerated (except two patients who discontinued the medication due to toxicities) at the proposed dosage, it was largely ineffective as monotherapy
It is discussed under MTKI section.
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[Mason et al., 2012]. Sorafenib, is an oral MTKI that also targets B-Raf and C-Raf [Guan et al., 2011].
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Selective PI3K inhibitors include XL-147, buparlisib and BKM120. XL147 (SAR245408) is a
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selective and reversible class I PI3K inhibitor that has been used in an exploratory trial in patients with recurrent GBM who were surgical candidates (NCT01240460). Buparlisib (NVP-BKM120) is a selective PI3K inhibitor demonstrated antitumor activity in U87 glioma cells [Koul et al., 2012]. BKM120 is currently under investigation in a phase II study with recurrent GBM patients (NCT01339052), a phase I dose escalation trial along with TMZ/RT in newly diagnosed GBM (NCT01473901) and a phase I/II study in combination with bevacizumab in patients with relapsed/recurrent GBM (NCT01349660). GBM patients who carry mutant PIK3R1 alleles may benefit from targeted inhibition of AKT since signaling through PI3K promotes tumorigenesis [Quayle et al., 2012]. MK-2206, an allosteric AKT inhibitor, is currently undergoing phase I/II trials [Hirai et al., 2010]. Perifosine (KRX-0401) is a novel Akt inhibitor. It has been evidenced to inhibit multiple intracellular signaling pathways in glial progenitors and cooperates with TMZ to arrest glioma cell proliferation in vivo [Momota et al., 2005]. It does not seem to be able to enhance the radiosensitivity of human glioma cells [De la Pena 22
ACCEPTED MANUSCRIPT et al., 2006]. Also, perifosine in combination with temsirolimus shows synergism in inducing apoptosis and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine GBM cells [Pitter et al., 2011]. Currently an ongoing phase I/II study seeks to investigate the combination
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of temsirolimus plus perifosine in recurrent or progressive malignant gliomas (NCT01051557) and a phase II study investigates perifosine monotherapy in recurrent/progressive malignant gliomas
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(NCT00590954).
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mTOR inhibitors used in malignant gliomas are either selective (e.g. temsirolimus, sirolimus, everolimus, ridaforolimus) or dual PI3k/mTOR inhibitors (XL-765, PI-103, PKI-587). Temsirolimus
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(CCI-779) is a specific mTOR inhibitor. In a phase II trial of temsirolimus against recurrent GBM,
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radiographic response in 36% of patients, PFS-6 7.8%, median OS4.4 months, median TTP 2.3 months (responders: 5.4 months vs non-responders: 1.9 months) were observed. It was generally well tolerated [Galanis et al., 2005]. In a second phase II study of temsirolimus on recurrent GBM
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no efficacy was demonstrated, though 50% of patients were initially stable. Once again the toxicity
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profile was well tolerated [Chang et al., 2005]. However, temsirolimus in combination with TMZ/RT
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showed increased risk of infectious complications [Sarkaria et al., 2010]. Various combinations have been either in ongoing trials or in completed ones. Sirolimus (rapamycin, AY-22989, WY-090217), is a selective mTOR inhibitor. It was found to achieve a partial radiographic response in 6% and stable disease in 38% of patients when combined with gefitinib, in a phase I study. Dose limiting toxicity included mucositis, diarrhea, thrombocytopenia and hypertriglyceridemia [Reardon et al., 2006]. In a phase II trial, combination of elrotinib and sirolimus in patients with recurrent GBM was ineffective and demonstrated a dismal PFS-6 of 3.1% but was generally well tolerated [Reardon et al., 2010]. Everolimus (RAD001) is an mTOR inhibitor of FKBP12. In a phase I trial of everolimus and temozolomide in combination with radiotherapy was found to be well tolerated in newly diagnosed GBM patients [Sarkaria et al., 2011]. A phase II study of concurrent TMZ/RT/bevacizumab followed by bevacizumab/everolimus following surgical resection in newly diagnosed GBM patients, demonstrated PFS of 11.3 months and median OSof 13.9 months. This efficient regimen was associated with everolimus related dose limiting toxicities like fatigue, pneumonitis and stomatitis. 23
ACCEPTED MANUSCRIPT Bevacizumab related side-effects were also observed. However, the PFS is favorable to standard TMZ/RT historical reports [Hainsworth et al., 2012]. Ridaforolimus (Deferolimus, AP23573, MK8669) is a selective mTOR inhibitor. In a phase II study on progressive or recurrent malignant
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gliomas, ridaforolimus given perisurgically was found to be able to cross the blood-brain barrier and with histological evidence it achieved mTOR inhibition, with an expected, well tolerated and no
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dose-limiting toxicity profile [Reardon, 2012 b]. A phase I safety study of ridaforolimus is completed
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in progressive/recurrent gliomas (NCT00087451). XL765 is a dual inhibitor of PI3K/mTOR that has been studied in vivo and in vitro against GBM cells and demonstrated efficacy both alone and in
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combination with TMZ [Prasad et al., 2011]. Two ongoing phase I studies use XL765, (a) in
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combination with TMZ with or without RT in malignant gliomas (NCT00704080) and (b) along with XL147 in surgical candidates with recurrent GBM (NCT01240460). PI-103 is a potent, cell permeable, ATP-competitive class I PI3K inhibitor and mTORC1/2 inhibitor. It was found to be
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efficient against malignant glioma xenografts [Fan et al., 2006]. PKI-587 (PF-05212384) is a dual
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PI3K/mTOR inhibitor that was found to be effective against glioma U87 cell lines [Mallon et al.,
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2011] and is now investigated in a safety phase I study. Two novel ATP-competitive mTOR inhibitors CC214-1 and CC214-2 suppress rapamycin resistant mTORC1 signalling, block mTORC2 especially in EGFRvIII activated GBMs. It also seems that autophagy helps cancer cells to overcome mTOR inhibition [Gini et al., 2013].
Enzastaurin (LY317615), a potent PKC inhibitor has been trialed against malignant gliomas. A phase I/II study of enzastaurin monotherapy in malignant gliomas demonstrated 25% radiographic response with PFS-6 of 7% (in GBM) and of 6% (in anaplastic glioma). Glycogen synthase kinase-3 in peripheral blood mononuclear cells was identified as a potential marker for drug activity [Kreisl et al., 2010]. However, a later phase III study comparing enzastaurin with lomustine in recurrent intracranial GBM did not show superior efficacy although it was less hematologically toxic [Wick et al., 2010]. A phase II study of TMZ plus enzastaurin during and after RT in newly diagnosed GBM was well tolerated and exhibited a median OSof 74 weeks which was positively correlated with MGMT methylation status and a median PFS of 36 weeks [Butowski et al., 24
ACCEPTED MANUSCRIPT 2011]. Enzastaurin before and concurrently with RT, followed by enzastaurin mainentance therapy in the newly diagnosed MGMT unmethylated GBM, demonstrated median OS of 15 months and PFS-6 of 53.6% (less than primary planned outcome) while it was well tolerated [Wick et al., 2013].
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A phase II trial of enzastaurin and bevacizumab in recurrent GBM is underway (NCT00586508). Tamoxifen, an antiestrogen, has been long described to act also as a PKC inhibitor [Baltuch et al.,
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1993]. Generally, tamoxifen has not been proved to be effective in the treatment of malignant
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gliomas [Spence et al., 2004]. In a phase II trial of RT plus high dose tamoxifen in GBM the median survival time was 9.7 months with a lower than expected thromboembolic incidence, a fact
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attributed to the PKC inhibitory effects of tamoxifen [Robins et al., 2006].
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Cyclopamine, is a specific SHH signaling pathway antagonist of Smoothened (SMO). In vitro studies show that it leads to depletion of stem-like cells in GBM [Bar et al., 2007]. Also, it produces a significant but incomplete GBM xenograft cell regression [Sarangi et al., 2009]. SEN450, a novel
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Smoothened receptor antagonist, seems to be cytostatic on its own and it further reduces tumor
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volume after TMZ pretreatment in vivo and in vitro [Ferruzzi et al., 2012]. Vismodegib (GDC-0449,
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HhAntag691), is a potent novel and specific SHH pathway inhibitor. It has been granted FDA approval for basal cell carcinoma [Meiss et al., 2014]. Vismodegib is being investigated in a phase II study of patients with recurrent GBM that are operatable (NCT00980343). Erismodegib (LDE225), a novel oral SHH pathway inhibitor and a selective Smoothened antagonist, suppresses epithelialmesenchymal transition and self-renewal of GBM cells through modulation of miRNA-200, -128 and -21 [Fu et al., 2013]. Gamma secretase inhibitors (GSIs) are investigated in malignant gliomas to block the Notch mathway [Stockhausen et al., 2012; Lin et al., 2010]. RO4929097 is an oral GSI that sensitizes GBM cells to TMZ in vivo and in vitro [Hiddingh et al., 2014]. It is under evaluation in recurrent/progressive GBM (phase II, NCT01122901). MK-0752 is a moderately potent gamma secretase inhibitor. It has been used in a phase I study of children wth refractory CNS malignancies and was well tolerated [Fouladi et al., 2011]. DAPT (GSI-IX) is a novel GSI that suppresses GBM growth in xenografts via uncoupling of tumor vessel density from vessel function as evidenced by 25
ACCEPTED MANUSCRIPT poor perfusion and aggravated hypoxia [Zou et al., 2013]. Recently, a study showed that alpha secretase inhibitors (ASIs) may be an alternative to GSIs in GBM since it decreased Notch activity and tumor size and increased survival time (compared to GSIs) in GBM cells [Floyd et al., 2012].
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Cilengitide (EMD121974) is a synthetic Arg-Gly-Asp pentapeptide (RGD) that recognizes the RGD ligand binding site on the integrin receptors αVβ3 and αVβ5 and competitively blocks integrin
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ligand binding [Reardon et al., 2008 a]. A phase II study of cilengitide in patients with recurrent
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GBM, demonstrated a PFS-6 of 15% and median OSof 9.9 months. It was generally well tolerated [Reardon et al., 2008 b]. A phase I/IIa study on cilengitide and TMZ/RT followed by the
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administration of cilengitide and TMZ as maintenance was conducted in newly diagnosed GBM,
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according to MGMT status of the patients. Results showed PFS-6 in 69% and PFS at 12 months in 33% of patients, median PFS at 8 months, OSof 68% (at one year) and 35% (at 2 years) and median OSof 16.1 months. PFS and OS were longer in patients with MGMT promoter methylation. The
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combination was well tolerated [Stupp et al., 2010 a]. A similar phase II study to verify the safety of
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cilengitide plus standard chemoradiation (TMZ/RT) also in newly diagnosed GBM was performed.
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The suggested dose was 2000mg and in this group, the median survival was 20.8 months, and regarding MGMT methylation status median survival was 30 months in patients with methylated MGMT and 17.4 months in the unmethylated status subgroup. It was generally well tolerated [Nabors et al., 2012]. In NABTC 03-02 phase II trial evidence of the efficacy of cilengitide was found to be modest as monotherapy in recurrent GBM while it was adequately delivered into the tumor [Gilbert et al., 2012]. Completed trials with cilengitide include, (a) cilengitide, TMZ and RT in newly diagnosed GBM and MGMT promoter methylation (phase III – CENTRIC trial- NCT00689221), (b) cilengitide, TMZ, RT in newly diagnosed GBM and unmethylated MGMT promoter (phase II – CORE trial – NCT00813943), and (c) Cilengitide in patients undergoing surgery for recurrent or progressive GBM (NCT00112866). Results are pending. Thalidomide has been considered as an older antiangiogenic agent [Wen et al., 2008]. It has been associated specifically with a decrease in the expression of adhesion molecules and especially integrins and thus is postulated to inhibit cell migration with antiangiogenic and anti-inflammatory 26
ACCEPTED MANUSCRIPT (decrease in leukocyte migration) activity [McCarty et al., 1997]. It is also widely known for its teratogenic potential. Generally, thalidomide has shown to be ineffective in malignant gliomas alone or in various combinations. In a phase II study of thalidomide plus irinotecan in newly
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diagnosed GBM showed limited efficacy compared to the standard approach while venous thromboembolism was common [Fadul et al., 2008]. In a phase II study on thalidomide combined
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with RT in newly diagnosed GBM did not improve survival [Alexander et al., 2013]. Studies with the
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more potent analogue of thalidomide, lenalidomide are under way including a combination of lenalidomide along with RT in newly diagnosed GBM (NCT00165477). In a phase I trial, lenalidomide
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monotherapy did not seem to be efficient with the added risk of thromboembolic disease [Fine et
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al., 2007]. Increased thromboembolic risk was also found in a phase I study of lenalidomide plus RT in newly-diagnosed GBM [Drappatz et al., 2009].
Multitargeted tyrosine kinase inhibitors (MTKIs): Many tyrosine kinase inhibitors can
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antagonize more than one type of kinase, thus it is somewhat arbitrary to classify them. However,
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most MTKIs do tend to have a more predominant inhibitory action against a specific type of kinase.
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MTKIs with effect on EGFR TKI include two reversible inhibitors (lapanitib and vandetanib) as well as an irreversible inhibitor (Bay846). Lapatinib (GW572016) is a reversible MTKI with dual action on EGFR/ERbB-1 and Her-2/ERbB2 family of receptors. In a phase I/II trial in recurrent GBM, did not show any significant efficacy and when given with anti-epileptic medication, its clearance increased about 1,000%. Neither EGFRvIII excpression, nor PTEN loss could predict a favorable subtype [Thiesen et al., 2010]. It has been used along with temozolomide in a phase I trial without any considerable efficacy [Karavasilis et al., 2013]. Lapatinib has also been investigated in combination with pazopanib and is being investigated along with TMZ and radiation therapy in patients with newly diagnosed GBM (NCT01591577). Vandetanib (ZD6474), is a reversible MTKI with action against EGFR, VEGFR-2, -3 and RET. In tumor models, it achieved higher reduction of GBM tumor volume when combined with TMZ than as monotherapy [Jo et al., 2012]. It has already been through phase I and II trials in patients with recurrent GBM that received fractionated radiosurgery [Fields et al., 2012; Kreisl et al., 2012] and it seems to be effective against gliomas 27
ACCEPTED MANUSCRIPT that express the EGFRvIII mutant, too [Yijn et al., 2010]. Autophagy protects glioblastoma cells from the proapoptotic effects of vandetanib and thus it might contribute significantly to the resistance against it [Shen et al., 2013]. Bay846 is a novel irreversible MTKI against EGFR and Her2 and shows
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efficacy in malignant glioma brain tumor cells. Bay846 was more efficient compared to lapanitib and its sensitivity was associated with wild type PTEN in conjuction with the expression of EGFRvIII
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[Longo et al., 2011].
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MTKIs with effevt on VEGFR include cabozanitinib, cediranib, E7080, pazopanib, sorafenib, sunitinib, vandetanib and vatalanib. Cabozantinib (XL184), is a MTKI that inhibits VEGF2, c-MET,
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AXL, TIE2, Flt-3 and RET. In a phase II trial as monotherapy, in the cohort that received the 175mg
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daily dose it showed a response rate of 21% and in the cohort with the better tolerated 125mg daily dose showed PFS-6 in 25% of patients. XL184 also appeared to have modest activity in patients with prior antiangiogenic treatment. It was noted that only a small number of patients developed distant
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or diffuse disease when the neoplasm progressed, indicating antiangiogenic plus anti-invasive
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effects of XL184 [Wen et al., 2010]. Cabozantinib, is probably a promising agent that suppresses
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angiogenesis, tumor growth and metastasis in neoplasms with dysregulated VEGFR and MET signaling [Yakes et al., 2011]. Moreover, two phase II studies on cabozantinib in recurrent (NCT00704288) and newly diagnosed (NCT00960492) GBM are under way. Cediranib, an oral MTKI, antagonizes all VEGFRs (especially VEGFR2), c-Kit and PDGFR. In a phase II study, used as monotherapy in patients with recurrent GBM, it exhibited encouraging results including PFS -6 in 26% of patients, median OSof 7 months and median PFS of 3.5 months. More than half of patients showed radiographic improvement. However, dose reduction or drug interruption was required in over half of the patients due to grade ¾ toxicities such as hypertension (12.9%), diarrhea and fatigue [Batchelor et al., 2010]. Later, a randomized phase III study, compared cediranib as monotherapy or in combination with lomustine to lomustine monotherapy (with cediranibmatched placebo, as control) was performed. Cediranib was used at lower doses relative to the previous phase II study (30 mg/day p.o. as monotherapy or 20 mg/day p.o. when combined with lomustine) and lomustine was administrated p.o. at 110mg/m2. Both monotherapies and 28
ACCEPTED MANUSCRIPT combinations were given every 6 weeks. The PFS-6 in the ceriranib monotherapy arm was lower than the one observed in the previous phase II study (16%). PFS-6 was 34.5% in the combination arm and 24.5% in the control arm [Ahluwalia et al., 2011]. The efficacy of cediranib in gliomas,
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seems to be limited by effective efflux at the brain-blood barrier via P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) [Wang et al., 2012]. Lenvatinib (E7080), an MTKI active
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against VEGF, PDGF and FGF receptors, suppresses tumor cell migration and invasion [Glen et al.,
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2011]. It is currently being investigated in a phase I/II study of the combination of E7080 plus E7050 (a dual c-MET and VEGFR-2 TKI) in patients with recurrent GBM (NCT01433991). Pazopanib
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(GW786034) is an MTKI against VEGFR-1 through -3, PDGFRα/β and c-Kit. In a phase II study on
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patients with recurrent glioblastoma, it was given at 800mg/daily in 4 week cycles. It was generally ineffective with a response rate of just 6%, PFS-6 of 3%, median PSF of 3 months and median survival of 35 weeks. However, radiographic response was observed. It was well tolerated with a
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toxicity profile similar to that of other anti VEGFR agents [Iwamoto et al., 2010 b]. A phase II study
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on pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma has
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demonstrated limited therapeutic results [Reardon et al., 2013]. Sunitinib, another MTKI, is antagonizing VEGFR-1, -2, -3, c-Kit, PDGFRα/β, Flt-3 and colony stimulating factor 1 receptor 9 (CSF1R). It is approved for gastrointestinal stromal tumors (GISTs) and advanced renal cancer [Gan et al., 2009]. In a phase I study on 25 patients with recurrent high-grade gliomas treated with sunitinib plus irinotecan, limited results were demonstrated with radiographic response was noted in only in one patient and PFS -6 months was 25% [Reardon et al., 2011 b]. In a phase II trial of patients with recurrent high grade glioma, although radiographic response was noted, clinical reponse was achieved in none with OSof 3.8 months [Neyns et al., 2011]. In a prospective phase II study, sunitinib monotherapy in patients with recurrent malignant gliomas (GBM or anaplastic astrocytoma) was disappointing and ineffective since it showed zero response rates, and PSF at 6 months of 16.7% and median OS12.6 months in GBM [Pan et al., 2012]. Vatalanib (PTK787/ZK222584)), is an oral VEGFR, PDGFR and c-Kit inhibitor. In a phase I study on vatalanib plus imatinib plus hydroxyurea in recurrent malignant glioma patients, it was found to be well 29
ACCEPTED MANUSCRIPT tolerated at 1000mg b.i.d. [Reardon et al., 2009 b]. In a 2010 phase I/II study on RT plus concomitant/adjuvant TMZ plus vatalanib/ZK222584 in patients with newly diagnosed GBM, the combination was found to be well tolerated and safe. However, the study was discontinued
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because the industry that was developing vatalanib, chose not to carry on and withdrew it [Brandes et al., 2010].
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MTKIs with effect on PDGFR include bosutinib, cediranib, dasatinib, imatinib, nilotinib,
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pazopanib, sorafenib, sunitinib, tandutinib. Bosutinib (SKI-606), inhibits PDGFR, Src/Srk and BCR/ABL tyrosine kinase used in the treatment of chronic myeloid leukemia [Rassi et al., 2013] and
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is currently being evaluated in a phase II study of patients with recurrent GBM (NCT01331291).
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Dasatinib, is an oral MTKI that affects BCR-ABL, the Src family, c-Kit, EPHA2 and PDGFR-β. It binds to both active and inactive ABL kinase domains. It induces apoptosis, auptophagic cell death of GBM cells, inhibits their invasion, alter cell adhesion and motility-migration of GBM cells in vitro. In vitro
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findings are being followed by ongoing preclinical trials in GBM including, (a) dasatinib plus RT/TMZ
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in newly diagnosed GBM, and (b) dasatinib monotherapy in recurrent GBM [Manmeet et al., 2010].
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Dasatinib plus lomustine in recurrent GBM was marked by significant hematological toxicity and suboptimal efficacy [Fransceschi et al., 2012]. A phase I trial of dasatinib plus erlotinib in patients with recurrent malignant gliomas, showed that it is a safe combination on a daily continuous dosing schedule. However no radiographic response was observed and the PFS-6 was 2%. No grade ¾ toxicities were observed and most commonly, dose limiting toxicities were diarrhea and fatigue [Reardon et al., 2012 a]. Dasatinib, does not appear to have any effect in combination with bevacizumab after bevacizumab failure in recurrent heavily pretreated GBM [Lu-Emerson et al., 2011]. P-gp and Bcrp seem to cause active efflux of dasatinib from the brain hence decreasing efficacy [Agarwal et al., 2012]. Imatinib is an oral MTKI that is effective against BCR-ABL, stem cell factor (SCF)/c-Kit, and PDGFR-α/β. Its toxicity profile includes myelosuppression, aplastic anemia, GI effects (nausea, vomiting, diarrhea, GI hemorrhage), liver toxicity (elevated transaminases/ bilirubin), respiratory effects (cough, dyspnea, upper respiratory tract infections, chest pain, pulmonary fibrosis), skin manifestations (erythema multiforme/ Stevens-Johnson syndrome, 30
ACCEPTED MANUSCRIPT pruritus, angioedema), nervous system effects (headache, migraines, central nervous system hemorrhage, peripheral neuropathy, syncopy), fatigue, pyrexia, blurred vision, conjunctivitis, ascites, fluid retention-edema, arthralgias/myalgias and electrolyte disturbances. It is metabolized
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through CYP 3A4 and subjective to drug interactions when this enzyme is induced [Gan et al., 2009]. In a 2005 phase II study, imanitib plus hydroxyurea in adults with recurrent GBM showed 9%
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radiographic response, PFS-6 in 27% of patients and median PFS 14.4 weeks, in a median follow up
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of 58 weeks. It was generally well tolerated and effective in some patients [Reardon et al., 2005]. However, in a later phase I/II study, imatinib mesylate when used in recurrent malignant gliomas as
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monotherapy was largely ineffective with a PFS-6 of 3% for GBM patients. CYP3A4 inducers
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substantially decreased its effectiveness [Wen et al., 2006 b]. In a phase II study the efficacy of imatinib monotherapy in patients with recurrent malignant gliomas was tested. Imatinib was generally well tolerated in the doses that it was administrated and demonstrated limited antitumor
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effects with a PFS-6 of 16% in GBM [Raymond et al., 2008]. In another phase II study imatinib was
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given as neoadjuvant imatinib before either definitive surgery or re-biopsy in GBM cases. Median
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survival was found to be 6.2 months. Imatinib was found in the histological specimens but it was not associated with reduction in either proliferation or other survival mechanisms (according to biochemical evidence of Ki67, AKT, MAPK or p27 level changes) [Razis et al., 2009]. During the same year, a multicentre phase II study of the combination of imatinib plus hydroxyurea in patients with progressive GBM was not found to be associated with clinically important antitumor activity but was well tolerated. PFS-6 was 10.6%, median OSwas 26 weeks and radiographic response was noted in 3.4% of cases. 7% of patients had either grade 3 fatigue, neutropenia, thrombocytopenia [Reardon et al., 2009 a]. Since the combination of hydroxyurea and imatinib had shown mixed results, in 2010, a randomized multicenter open label phase III study was carried out comparing the combination of hydroxyurea plus imatinib versus hydroxyurea alone in patients with recurrent progressive GBM resistant to TMZ. No clinically important differences were found in comparing the two arms thus implying the ineffectiveness of imatinib in recurrent GBM. The median PFS was similar in both arms (6 weeks), and PFS-6 was 5% for the combination arm and 7% for the 31
ACCEPTED MANUSCRIPT monotherapy arm. In the arm with imatinib, toxicities were well tolerated [Dresemann et al., 2010]. Nilotinib, another PDGFR, BCR-ABL and c-Kit inhibitor, is used in chronic myeloid leukemia [Jabbour et al., 2012] and is currently being investigated in a phase II study of patients with recurrent
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malignant gliomas (NCT01140568). Tandutinib (MLN518), a PDGFR, Flt-3 and c-Kit inhibitor [Lehky et al., 2011], has been evaluated in a phase II trial of the combination tandutinib plus bevacizumab
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in recurrent malignant gliomas. The trial is completed and the results are pending (NCT00667394).
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A second study on tantutinib combination in recurrent or progressive GBM is also completed (NCT00379080).
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MTKIs with action against HGF/SF include cabozantinib, crizotinib and MP470. Crizotinib
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(PF02341066), a dual c-MET, ALK inhibitor, has been tried in patients with both c-MET and ALK positive histology. Recently, there was a report of rapid radiographic and clinical improvement after treatment with crizotinib in MET-amplified recurrent GBM [Chi et al., 2012]. Amuvatinib (MP470), a
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novel oral potent c-Met, c-Kit and PDGFR inhibitor has been shown to radiosensitize GBM cells both
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in vivo and in vitro [Welsh et al., 2009]. Three different safety phase I trials have already been
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completed in healthy volunteers [Choy et al., 2012]. Sorafenib is an oral MTKI with targets such as VEGFR-2, -3, Flt-3, PDGFR-β, c-Kit and it also inhibits B-Raf and C-Raf. These inhibitory effects decrease tumor cells and angiogenesis. This drug is commonly used in hepatocellular carcinoma [Guan et al., 2011]. In vitro results of sorafenib plus nutritional factors such as vitamin K1, has demonstrated enhancement of growth inhibition and apoptosis of malignant glioma cells by blocking the Raf/MEK/ERK pathway [Du et al., 2012]. A phase I trial on concurrent RT and TMZ followed by TMZ and sorafenib in newly diagnosed GBM did not appear to improve efficacy compared to historical standard therapy results [Hainsworth et al., 2010]. In a Phase II study, patients with recurrent GBM were treated with sorafenib plus daily TMZ. However, PFS-6 was only 9.4% (only one patient achieved partial response) and this was attributed to drug interactions with CYP3A inducing antiepileptic drugs that lowered sorafenib exposure in these patients [Reardon et al., 2011 c]. In a phase I/II trial with patients with recurrent GBM, the combination of temsirolimus plus sunitinib was discontinued due to zero PFS-6 [Wen et al., 2009]. A 32
ACCEPTED MANUSCRIPT phase II trial of erlotinib along with sorafenib in patients with recurrent or progressive GBM did not have acceptable results as there were pharmacokinetic interactions between the two drugs [Peereboom et al., 2013]. A phase I/II trial of sorafenib combined with erlotinib, tipifanib or
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temsirolimus in recurrent GBM has been completed (NCT00335764). Other molecular targets and drugs: The importance of epigenetic alterations in cancer is
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well appreciated. Histone deacetylases (HDAC) are involved in chromatin structure that organize
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DNA and regulate transcription of genes and are altered in malignant gliomas. HDAC inhibitors have been used in an attempt to halt growth arrest and to promote cancer cell apoptosis. Histone
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acetylases (HATs) and histone hyperacetylation can also degrade HIF-1a and decrease VEGF and
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thus can lead to antiogenetic effects [Galanis et al., 2009]. Treatment with HDACs reduces proliferation of glioblastoma-derived stem cells and induces their differentiation [Alvarez et al., 2014]. Vorinostat (SAHA) is an oral quinolone-based HDAC inhibitor that in a phase II study as
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monotherapy in recurrent GBM demonstrated modest activity with median OSof 5.7 months and
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PFS-6 was achieved in 9 of the first 57 patients (total of 66). Toxicities included hematologic grade 3
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or worse (mainly thrombocytopenia) as well as grade 3 or worse nonhematologic toxicities (fatigue, dehydration, hypernatremia) [Galanis et al., 2009]. Vorinostat in combination with TMZ in high grade gliomas seems to be well tolerated [Lee et al., 2012]. Many trials with vorinostat are ongoing including a phase I/II trial of vorinostat plus TMZ/RT in newly diagnosed GBM (NCT00731731) and in various combinations such as with isotretinoin plus TMZ or bevacizumab plus TMZ/RT. However, it seems that inhibition of HDAC potentiates the evolution of TMZ resistance by MGMT overexpression in vitro [Kitange et al., 2012]. Panobinostat (LBH589) another HDAC inhibitor has been tested in patients with recurrent high-grade gliomas in combination with bevacizumab in a phase I trial, while a phase II study is ongoing [Drappatz et al., 2012]. Romidepsin (FR901228, Depsipeptide), another quinolone-based HDAC inhibitor has been evaluated in a phase I/II trial of patients with recurrent malignant glioma. It was largely ineffective with a median PFS was 8 weeks, PFS-6 was 3% and median survival duration was 34 weeks [Iwamoto et al., 2011]. Trichostatin A
33
ACCEPTED MANUSCRIPT (TSA) is an HDAC inhibitor that promotes apoptosis on GBM cells and potentiates innate immune response against cancer cells in vitro and in vivo [Höring et al., 2013]. Heat shock proteins (Hsp) and specifically Hsp90 are molecular chaperons that assist in
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stabilizing client proteins such as protein kinases and several transcription factors. Hsp90 seem to be vital in maintaining malignant transformation and in increasing the growth, survival and
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invasiveness of cancer cells. It stabilizes surface expression of EGFRvIII and EGFRvIV mutants and
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probably maintains invasiveness of GBM [Pines et al., 2010]. Tanespimycin (17-AAG) is a potent Hsp90 inhibitor. It exhibits in vitro inhibition of GBM cells and synergistic effects with radiation. It
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can also attenuate glioma stem cell radioresistance but not with TMZ [Sauvageot et al., 2009].
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Acquired resistance is found during prolonged exposure of tanespimycin [Gaspar et al., 2009]. The 26S proteasome is a protein complex that degrades ubiquinated proteins. The role of the ubiquitin-proteasome pathway is to regulate intracellular concentrations of specific proteins
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and maintain cellular homeostasis as it is related to regulation of the cell cycle and transcription,
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cell signaling and apoptosis by degrading regulatory proteins such as p53 and cyclin dependent
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kinases or CDKs [Mani et al., 2005]. Bortezomib (PS-341) is a selective reversible inhibitor of the 26S proteasome. In a phase I of recurrent malignant glioma patients, some clinical efficacy was observed. The overall response rate was 3%, PFS-6 was 21% for patients without exposure to enzyme inducing antiepileptics-EIAED and 9% for those exposed, and median PFS was 1.9 months (exposed) versus 2.6 months (for non-exposed). Median OS was 5.8 months (in EIAED exposed patients) versus 6.1 months (in EIAED non-exposed patients [Phurphanich et al., 2010]. A phase II trial of the combination of vorinostat plus bortezomib in recurrent GBM was disappointing and demonstrated an OS of 3.2 months and median TTP of 1.5 months [Friday et al., 2012]. Bortezomib has shown to overcome MGMT-related resistance of GBM cells to TMZ in vitro by inhibiting MGMT with scheduling of administration being critical (bortezomibe should be given prior to TMZ) [Vlachostergios et al., 2013]. Bortezomib acts synergistically along with HDAC inhibitors to eliminate GBM stem-like cells [Asklund et al., 2012]. Marizomib (NPI-0052) is a new proteasome inhibitor that
34
ACCEPTED MANUSCRIPT has been tested in models for glioma [Potts et al., 2011]. The proteasome inhibitor MG132 produces apoptosis of GBM cells and acts as a chemosensitizer in vitro [Zanatto-Filho et al., 2012]. Tranforming-growth factor beta (TGF-β) and in particular the β2 isoform, is considered a
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key factor in malignant glioma progression (TGF-β2 was originally described as “glioblastomaderived T-cell suppressor factor”) and is associated to be associated with the depressed immune
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status of patients with GBM. High plasma and tissue levels of TGF-β2 are associated with poor
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prognosis and advanced disease [Hau et al., 2011]. It seems to also have an essential role in regulation of glioma-stem cells through Smad-dependent induction of LIF and the subsequent
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activation of JAK-STAT pathway [Penuelas et al., 2009]. Trabedersen (AP 12009) an antisense
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oligonucleotide that specifically inhibits TGF-β2mRNA was tried as monotherapy (administered intratumorally by convection enhanced delivery) versus standard chemotherapy (TMZ or PCV) in a recently randomized phase IIb study, of patients with recurrent or refractory malignant gliomas. At
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10 μM, it achieved a median survival of 39.1 months compared with 21.7 months for chemotherapy
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[Bogdahn et al., 2011]. LY2109761 is a TGF-beta receptor I kinase inhibitor that seems to act as a
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radiosensitizer and prolongs survival in vitro and in vivo [Zhang et al., 2011] and may be used as an adjunct to RT/TMZ in GBM [Zhang, Herion et al., 2011]. SRC and SRC-family kinases (SFKs) mediate downstream signaling pathways from several growth factor receptors and they are frequently activated in glioblastoma [Wick et al., 2011]. It is supported that increased invasiveness associated with antiangiogenic treatment with VEGF inhibitors, is mediated through increased SFK signaling and thus, justifying the combination of dasatinib with bevacizumab [Huveldt et al., 2013], however without much success [See dasatinib]. Glutamate was until recently unrecognized as significant in the pathogenesis of the gliomas. Glutamate is produced as a byproduct of glutathione synthesis and is released by the x(c) (-) cystine glutamate receptors in glioma cells. It is involved by either binding on peritumoral Glu receptors or by paracrine/autocrine effects in: a) in seizure induction, b) excitotoxicity, c) Akt/MAPK activation and cell invasion through AMPA receptors, d) inducing focal adhesion kinases, critical for growth factor regulation and integrin-stimulated cell motility/invasion [de Groot and Sontheimer, 35
ACCEPTED MANUSCRIPT 2011]. Talampanel, a well tolerated oral alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor blocker was tested in a phase II trial in patients with newly diagnosed GBM in addition to standard RT/TMZ. When compared with historical results with standard treatment, the
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median survival was 20.3 versus 14.6 months and 2 month-survival was 41.7% versus 26.5% favoring the addition of talampanel [Grossman et al., 2009]. In a phase II trial of talampanel
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monotherapy against recurrent malignant gliomas was disappointing but well tolerated with most
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common toxicities were fatigue, dizziness, ataxia and respectively results for GBM/anaplastic glioma were PFS-6: 4.6%/0%, median PFS: 5.9 weeks/8.9 weeks and OS: 13 weeks/14 months
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[Iwamoto et al., 2010 a]. Riluzole, a glutamate release inhibitor, in combination with LY341495, a
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groupie mGluR inhibitor, seems to act synergistically to inhibit the growth of GBM in vitro [Yelshkaya et al., 2013].
Topoisomerase I inhibitors camptothecin, irinotecan and novel NKTR-102 as well as
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topoisomerase II inhibitors etoposide and teniposide show in vitro efficacy against glioblastoma cell
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lines [Tamura et al., 2012]. Irinotecan and topotecan have been tested on GBM in various
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combinations including TMZ and bevacizumab with irinotecan and have shown some promising results [Sasine et al., 2010]. NKTR-102 is a topoisomerase I inhibitor polymer conjugate that releases irinotecan following administration and is further metabolized to SN-38, is currently being tested in a phase II study of bevacizumab resistant GBM (NCT01663012). Etoposide in a recent meta-analysis was found to improve OS more than iriotecan in patients with high grade gliomas [Leonard et al., 2013]. JAK2/STAT3 pathway, signal transducers and activators of transcription 3, inhibitors have recently risen as approaches for cancer immunotherapy. STAT3 is constitutively active in some GBM cells, helping tumor cells resist apoptosis and enhance local immunosuppression. The non-receptor tyrosine kinase BMX activates STAT3 signaling to maintain self renewal and tumorigenic potential of glioma stem cells and it can serve also as a therapeutic target [Guryanova et al., 2011]. WP1193 in vitro [Sai et al., 2012] and WP1066 in GBM patients [Hussain et al., 2007], are both effective by reducing glioma cell growth as well as reducing glioma stem cell lines. See also manumycin, a FTI. 36
ACCEPTED MANUSCRIPT Double stranded RNA (dsRNA) is an example of pattern recognition agonists. In a phase II study of the immune modulator polyinosinic-polycytifylic (poly-ICLC) acid in patients with recurrent anaplastic glioma, produced discouraging results: 11% radiographic response, PFS-6 24% and
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median survival of 43 weeks [Butowski et al., 2009]. A phase II study of the poly-ICLC plus standard TMZ/RT in newly diagnosed GBM patients, demonstrated improved results relative to historical
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data of standard regimens [Rosenfeld et al., 2010].
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Other experimental therapeutics: C-150, a novel curry spice curcumin nanoformulative derivative, is a multitargeted agent that reduces the transcription activation of NFkB, inhibits PKC-
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alpha, VEGF, Cyclin D1, BCL-XL and promotes differentiation of glioma-initiating cells by inducing
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autophagy in vitro and shows efficacy in vivo [Ozsvári et al., 2013]. When curcumin is coupled to a glioblastoma-directed antibody, it potentiates its antitumor activity [Langone et al., 2013]. Curcumin increases GBM cell sensitivity to TMZ by generating reactive oxygen species and by
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disrupting the AKT/mTOR pathway [Yin et al., 2014]. Niclosamide is an anthelminthic medication
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that has demonstrated anti-tumor effects in vitro, probably mediated through inhibition of
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WNT/CTNNB1-, Notch-, mTOR-, and NF-kB signaling pathways [Wieland et al., 2013]. Aprepitant is an oral neurokinin-1 receptor (NK-1R) antagonist used in treating nausea and vomiting. Substance P is a natural ligand of NK-1R and thus blockage of this pathway seems to inhibit proliferation, induce apoptosis, antiangiogenic and anti-magration effects in preclinical trials [Muñoz et al., 2012]. Artesunate, an antimalarial drug, induces oxidative DNA damage, DNA double-strand breakage and the ATM/ATR damage response in cancer cells [Berdelle et al., 2011] and potentiates erlotinib’s EGFR mediated cytotoxicity [Efferth et al., 2004]. Auranofin, a medication used to treat rheumatoid arthritis, inhibits cytoprotective thioredoxin reductase and cathepsin B. Thioredoxin reductase is upregulated by TNF-alpha-induced apoptosis (ATIA) protein in glioblastoma and protects from oxidative damage whereas cathepsin B promotes GBM growth and invasion, thus proposing auranofin as a GBM treatment adjunct [Kast et al., 2010]. Disulfiram is an oral aldehyde dehydrogenase (ALD) inhibitor and has strong anti-GBM effects. In vitro effects include Pglycoprotein inactivation, MGMT repair function inhibition, superoxide dismutase inhibition which 37
ACCEPTED MANUSCRIPT secondarily inhibits proteosome, induction of oxidative stress, inhibition of DNA methyltransferase, reduction of DNA replication and reduction of NF-kB pathway [Kast and Halatsch, 2012]. Nelfinavir, a protease inhibitor used in the treatment of HIV infection, exhibits anti-GBM potential by binding
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to and limiting the chaperone function of HSP90 [Kast et al., 2012]. Sertraline, an oral selective serotonine reuptake inhibitor (SSRI), demonstrates downregulation of AKT together with TMZ and
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imatinib in vitro [Tzadock et al., 2014]. Captopril, an angiotensin conversion enzyme inhibitor (ACEI)
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inhibits glioblastoma cell synthesis of MMP-2 and MMP-9 thus strongly inhibiting GBM growth and invasion [Tzadock et al., 2014]. Furthermore, GBM cells express AT-1R (67%) and AT-2R (53%) and
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this high expression is associated with a poor prognosis [Arrietta et al]. Coordinated undermining of
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survival paths (CUSP9) project is investigating aprepitant, artesunate, auranofin, captopril, disulfiram, nelfinavir, sertraline, ketoconazole and copper gluconate as adjuvant to low dose TMZ in patients with recurrent GBM [Kast et al., 2013].
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Monoclonal Antibodies: Monoclonal antibodies (MAbs), are targeting immunoglobulins
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that specifically recognize cell surface proteins/receptors as antigens, especially targeted on the
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surface of tumor cells. They are mainly classified on whether they are unconjugated or conjugated (to protein toxins/cytotoxic agents), or radioimmunoconjugates (to radioisotopes). Mabs may be of murine, human, primate or chimeric (murine variable region plus human constant region) origin [Harris et al., 2004]. Examples of anti EGFR chimeric MAbs are cetuximab and MAb 806, whereas examples of humanized MAb are nimotuzumab and panitumumab. Cetuximab, is an unconjugated chimeric murine-human IgG1 MAb which binds to the extracellular domain of the EGFR, thus inhibiting the binding of EGF to its receptor. It has a stronger affinity to EGFR (plus the EGFRvIII) than EGF and TGF-α. It also downregulates EGFR, inhibits cell growth and metastasis, induces apoptosis, inhibits VEGF production and causes antibody dependent cell-mediated cytotoxicity [Fukai et al., 2008]. In recurrent high grade glioma, cetuximab as monotherapy has demonstrated PFS-6 in 9.2% of patients, median OS(OS) of 5 months and average time to progression (TTP) of 2 months. Although patients where stratified according to EGFR amplification, no correlation to response was found [Neyns et al., 2009]. Again in the 38
ACCEPTED MANUSCRIPT recurrent GBM setting, the combination of bevacizumab, irinotecan and cetuximab showed PFS-6 in 30% of patients, median OS 7.2 months and radiographic response of 34% [Hasselbalch et al., 2010]. Amplification of EGFR and the type of EGFR mutation (EGFRvIII or EGFRvIV) may determine
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the outcome in GBM patients treated with cetuximab. Patients with EGFR amplification and lack of EGFRvIII had better OS (p=0.12) than patients with EGFRvIII expression (p=0.08) [Lv et al., 2012]. No
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trials have been publiced with cetuximab as treatment in newly diagnosed high grade gliomas up to
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this date. MAb 806, seems to enhance the efficacy of ionizing radiation in glioma xenografts expressing the EGFRvIII mutation and can inhibit the growth of U87MG [Johns et al., 2012].
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Nimotuzumab, a humanized MAb with preferential binding to high-EGFR-density tissues (e.g
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tumors, sparing normal tissue) has been tested in pediatric recurrent high grade gliomas [MackDonald et al., 2011]. Radiotherapy plus nimotuzumab or placebo in anaplastic astrocytoma and GBM demonstrated excellent safety profile and significant survival bebefit with mean survival
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of 31.06 months in nimotuzumab treated group versus 21.07 for the control group [Solomón et al.,
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2013]. A Chinese Phase II study of nimotuzumab in combination with TMZ/RT demonstrated good
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safety and tolerability without prolonging survival compared to standard therapy [Wang et al., 2014]. Panitumumab (ABX-EGF), a human monoclonal antibody specific for HER-1, has been used in combination with irinotecan for GBM but results have not been published (NCT01017653) [Berezowska et al., 2011]. AMG 595, an anti-EGFRvIII-DM1 immunoconjugate human monoclonal antibody is currently being evaluated in a phase I study patients with recurrent GBM expressing mutant EGFRvIII (NCT01475006). Anti-VEGFR MAbs include bevacizumab, ramucirumab (IMC-1121B) and IMC-18F1. Bevacizumab, is an unconjugated recombinant humanized murine MAb which binds to and neutralizes VEGF-A, preventing the activation of VEGF receptor tyrosine kinases VEGFR-1 and -2. Given i.v., it has an important toxicity profile. Common manifestations of toxicity include hypertension, headache, gastrointestinal effects (abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation), proteinuria, leucopenia, weakness, stomatitis, epistaxis, dyspnea, upper respiratory tract infection and impaired wound healing. Some more rare but severe side-effects are 39
ACCEPTED MANUSCRIPT central nervous system hemorrhage, venous and arterial thromboembolic events, bowel perforation, left ventricular dysfunction, infusion related reactions and nephrotic syndrome [De Fazio et al., 2012]. In the newly diagnosed setting of GBM, since the concern of serious toxicity is
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great enough, assessment of risk versus benefit is important. When patients with MGMT methylation is treated with RT and TMZ without bevacizumab, about 50% survive 2 years [Stupp et
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al., 2009]. So it is of concern whether the addition of bevacizumab will prolong this OSor shorten it
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due to toxicity. Also, there is concern that addition of bevacizumab promotes a more invasive and aggressive tumor hence shortening survival compared to RT/TMZ alone. In a way to avoid the risk, a
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stratification system has been employed to design GBM trials. The recursive partitioning technique
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(RPA) can be used. Preliminary data demonstrated that there is a trend towards longer survival (when compared to standard RT/TMZ treatment) for patients with low RPA class (e.g. poor performance status and older age) but not for patients with a high RPA class when bevacizumab is
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added. However, a longer PFS-6 was achieved with no association to RPA class [Curran et al., 1993;
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Lai et al., 2009]. In a phase II study which was compared the addition of bevacizumab to standard
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RT/TMZ versus standard treatment alone, showed PFS-6 in 77.5% versus 51.6% of patients respectively and median PFS 17 months versus 7 months respectively [Gruber et al., 2009]. A randomized trial of the addition of bevacizumab or placebo in newly diagnosed GBM, did not improve the OS(median 15.7 vs 16.1 months respectively) though it improved the PFS (10.7 vs 7.3 months) but increased symptom burden and the rate of adverse effects led to an attenuation in quality of life [Gilbert et al., 2014]. In the recurrent setting, bevacizumab has been evaluated either alone or in combination with other agents such as irinotecan, etoposide, carboplatin and TMZ. The phase II BRAIN study, evaluated the role of bevacizumab alone or in combination with irinotecan in patients with recurrent GBM. Monotherapy versus combination showed respectively PFS-6 in 42.6% versus 50.3% of patients, objective response 28.2% versus 37.8% and median OSof 9.2 versus 8.7 months. Both groups of patients had superior radiographic response rates, median PFS and PFS-6 in relation to historical controls [Friedman et al., 2009]. However, this study was a non-comparative study, so 40
ACCEPTED MANUSCRIPT it wasn’t designed to compare the two arms. A second study, tested patients with recurrent GBM treated with bevacizumab and it showed a response rate of 35%, PFS-6 in 29% of patients and a median OSof 31 weeks, decreases in cerebral edema, lower needs for corticosteroids and improved
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neurologic function. Patients that experienced later progression, did not show any improvement when irinotecan was added [Kreisl et al., 2009]. After the BRAIN study, there was still dispute on
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whether monotherapy of bevacizumab was of any real benefit but after the second forementioned
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study, FDA rushed into an accelerated approval in 2009 and since then, bevacizumab is the approved monotherapy for recurrent GBM. Clinical benefit was also demonstrated in Japanese
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patients with PFS-6 in 33.9% of patients, median PFS of 3.3 months and median overall survival of
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10.5 months [Nagane et al., 2012]. However, most patients progress and die from the desease within 6-9 months [Kang et al., 2008]. Patients with progression after bevacizumab failure, have no standard options for salvage treatment. Given the lack of effective salvage regimens, possible
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options include treatment, with bevacizumab again until a second or further recurrence in patients
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with high performance status and small non-rapidly enlarging tumors or combinations, with
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targeted therapies that inhibit possible resistance mechanisms such as other growth factors, or circulating progenitor cells [Krashraw et al., 2010]. Other combinations of bevacizumab have been tested such as plus etoposide or TMZ [Reardon et al., 2011 a], plus erlotinib [Sathornsumetee et al., 2007] and bevacizumab with dosedense TMZ [Gilbert et al., 2010]. However, response rate, PFS-6 and OSwhere similar to the bevacizumab monotherapy rates seen in BRAIN study. Ramucirumab (IMC-1121B) (NCT00895180) and Icrucumab (IMC-18F1) are newer monoclonal antibodies that target the VEGF receptors VEGFR-2 and VEGFR-1 respectively. Trials on GBM are under way but not published up to this date [Hsu et al., 2009]. Aflibercept [Hsu et al., 2009] (also known as VEGF trap), is a recombinantly produced soluble peptide-antibody fusion that scavenges VEGF ligand and placental growth factor. In patients with GBM, two separate phase II studies have been published [de Groot et al., 2011; GomezManzano et al., 2008]. Generally it showed minimal activity and specifically demonstrated PFS-6 in 41
ACCEPTED MANUSCRIPT 7.7% of patients, response rate of 18% and median PFS of 3 months [Gomez-Manzano et al., 2008]. Toxicity led to discontinuation of the treatment in a quarter of patients which included hypertension, lymphopenia, fatigue and central nervous system toxicity (cerebral ischemia).
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MAbs against PDGFR-α, include IMC-3G3 and MEDI-575. MEDI-575 is investigated in ongoing phase I/II studies in recurrent GBM patients (NCT01268566) and results are pending. IMC-
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with ovarian cancer (see NCT00895180) [Shah et al., 2010].
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3G3, has shown inhibition of growth (69%) in U118 GBM cell lines and has been tried in patients
Rilotumumab (AMG102), is a fully human MAb that effectively blocks c-Met
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phosphorylation, thus inhibiting c-Met activated signaling pathways [Giordano et al., 2009]. It has
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been shown to radiosensitize GBM cells in vivo and in vitro [Buchanan et al., 2011]. In a phase II study, patients with recurrent GBM treated with rilotunumab. Two cohorts were designed depending on the rilotunumab dose (10 and 20 mg/kg) and respectively median OSwas 6.5 months
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versus 5.4 months and PFS was 4.1 weeks versus 4.3 weeks. No significant statistical difference was
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attained regarding the pretreatment status with bevacizumab. The results were disappointing and
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the most common adverse effects were fatigue, headache and peripheral edema [Wen et al., 2011]. Two more phase II studies are currently underway evaluating the combination of AMG102 and bevacizumab in patients with recurrent malignant glioma (NCT01113398) as well as AMG102 monotherapy in advanced malignant gliomas (NCT00427440). Onartuzumab (MetMAb or OA-5D5), is a novel human, monovalent (one-armed) 5D5 (OA-5D5) anti-c-Met antibody that was found to be effective in reducing proliferation and microvessel density, as well as in increasing apoptosis in U87 GBM cells (c-Met and HGF/scatter factor positive cell lines) [Martens et al., 2006]. A phase II study of onartuzumab in combination with bevacizumab versus bevacizumab alone or onartuzumab alone in patients with recurrent GBM is in progress (NCT01632228). Stem cells: It has been noted earlier that glioma stem cells have proliferative, invasive capabilities and promote angiogenesis. EGFR inhibitors (that reduce the CD133+ population of stem cells), PI3K/Akt/mTOR pathway inhibitors, GSIs, anti-angiogenetic agents (e.g bevacizumab or cediranib to target the vascular niche of glioma stem cells), Notch pathway inhibitors, Hsp90 42
ACCEPTED MANUSCRIPT inhibitors, Sonic hedgehog pathway inhibitors have all been used to block glioma stem cell population and perhaps enhance radiosensitivity. Cell surface molecules on glioma stem cells may be used as pharmacological targets. L1CAM specifically is a glycoprotein that contains a cytoplasmic
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tail, a transmembrane domain and its extracellular domain that is preferentially found in glioma stem cells compared to non-stem cells of GBM tumors. It can either bind with extracellular matrix
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proteins, EGFR, FGFR, α5β1, avb3, neurophilin-1 or with another L1CAM molecule. L1CAM acts as a
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mediator of molecular signals and regulates survival, growth, adhesion, invasion and migration glioma stem cells. Some of its effects may be due to upregulation of Olig2 that suppresses
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p21WAF/CIP1 [Schmidt et al., 2008]. L1CAM expression is increased with mutations of TP53 or
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expression of TGF-beta [Tsuzuki et al., 1998]. L1CAM also contributes in the chemoresistance of GBM cells and stem cells [Held-Feindt et al., 2012]. Blocking L1CAM, seems to be able to suppress tumor growth and prolong survival of tumor cells in vivo [Bao et al., 2008].
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Since malignant gliomas contain many genetic alterations, various viral vectors have been
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employed to transmit therapeutic genes into their neoplasmatic cells and target those alterations.
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The replication oncolytic adenovirus Delta-24-RGD is capable of engaging the complete cellular system within the glioma cells for its own replication and survival. Even resistant glioma stem cells seem to be vulnerable, suggesting autophagy (upregulation of Atg5 in the tumor cells) followed by lysis of the malignant cell [Jiang et al., 2007]. A phase I/II trial in patients with recurrent GBM (NCT01582516) and a phase I trial for patients with recurrent malignant gliomas (NCT00805376) are ongoing. Immunotherapy: Immunotherapy is a promising approach that has demonstrated an ability to specifically eliminate cancer cells without damaging the surrounding healthy tissue. It includes passive and active immunotherapy strategies. Active immunotherapy creates a long-term immune response against the tumor (propably effective against recurrences) and passive immunotherapy involves the transfer of immediately and short-acting effecting molecules. Tumor-specific antigens are processed by antigen presenting cells (APCs) and recognized by lymphocytes. GBM has the
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ACCEPTED MANUSCRIPT ability to modulate the activity of APCs and this is hypothesized from vaccination studies using tumor lysates that have been unsuccesful [Jackson et al., 2013]. Passive immunotherapy utilizes monoclonal antibodies, adoptive cell transfer and cytokine-
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mediated therapies. Targeted monoclonal antibodies that were discussed in the above sections can be lethal to tumor cells by immune-mediated mechanisms as well as by their specific-targeted
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effects. MAbs bind on cancer cell surfaces in a major histocompatibility complex (MHC) unrestricted
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manner and induce GBM cell death by both immune and non-immune mechanisms. Nivolumab, a fully human MAb against programmed death receptor-1 (PD-1), a negative checkpoint regulator
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with immunosuppressive capabilities has been approved for treatment in unresectable malignant
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melanoma in Japan [Deeks et al., 2014]. Ipilimumab is a MAb that binds to cytotoxic T-lymphocyte (CTL)-associated antigen-4 (CTLA-4/CD152) and enhances T-cell activation thus allowing CTLs to destroy the cancer cells. It has been approved for used in malignant melanoma [Karimkhari et al.,
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2014]. Its efficacy in recurrent GBM is being investigated in a phase IIb trial as monotherapy or in
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combination with ipilimumab versus bevacizumab (NCT02017717).
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Adoptive cell transfer uses effector cells that are activated ex vivo and then tranfered to a patient to attack GBM cells. Effector cells can be lymphocyte-activated killer (LAK) cells, CTLs, natural-killer (NK) cells and γδ-T-cells. Results generally have been mixed with good tolerability but the OS was not significantly improved [Dillman et al., 2009]. Newer CTLs that are more specific to tumor-associated antigens like CD133 which show activity against GBM stem cells [Hua et al., 2011] or virus-specific CTLS (e.g. against CMV proteins pp65 and IE1-72 or nucleic acids) are intensively being investigated against GBM [Nair et al., 2014] (NCT00693095, NCT01109095). Genetically modified T-cells with novel artificial chimeric antigen receptors (CAR), can recognize antigens with HLA-independent mechanisms. CARs are fusion molecules of MAb specific for a tumor-antigen and the ζ-chain of the T-cell-receptor (TCR). CAR-modified T-cells have been manufactured against IL-13 receptor alpha 2 (IL13Ra2) [Krebs et al., 2014] and EGFRvIII [Choi et al., 2014]. A phase I/II trial of autologous CARs against EGFRvIII in glioblastoma is in development (NCT01454596). A phase I trial of postsurgical tumoral cavity injection of IL13Ra2 in GBM has been completed (NCT01082926). 44
ACCEPTED MANUSCRIPT Active Immunotherapy – Vaccine strategies: Although we have a vast arsenal of agents to attack the EGFRs in GBM, a large amount of EGFRs still cannot be blocked due to the receptor’s ubiquitous and high level expression. A peptide vaccine, rindopepimut (CDX-110), is directed
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against the novel exon 1-8 junction produced by the EGFRvIII mutation. Recent phase II studies have shown EGFRvIII specific immune response and significantly prolonged TTP and OS in patients
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with newly diagnosed GBM compared to standard care. It represents a promising field of therapy
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in patients with GBM [Del Vecchio et al., 2012]. A phase III study in patients with newly diagnosed GBM is under way [NCT01480479). ITK-1 is a personalized peptide vaccine given in HLA-A24
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positive recurrent or progressive GBM patients [Terasaki et al., 2011].
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Heat shock protein peptide vaccine (HSPPV) uses peptides complexed with Hsp proteins that are effectively used by APCs [See et al., 2011]. Vitespen a heat shock protein (gp96)-peptide complex purified from autologous tumors has been used in phase I/II trials with minimal side-
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effects and clinical responses in early-stage disease [Wood et al., 2009].
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Other peptide vaccines for malignant gliomas include peptides against melanoma/testis
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antigens, viral antigens, cytokine receptors and differentiation antigens [Mithell et al., 2009]. Gene-modified tumor vaccines work in a different way by inducing GBM cells to be more immunogenic, express new antigens and thus give more targets for the immune system to fight against. Using autologous glioma cells modified to secrete either granulocyte/macrophage colony factor (GM-CSF) [214] or TGFβ2 antisense vectors [Fakhrai et al., 2006] or IL-4 [Okada et al., 2007], response has been seen in small trials of progressive or recurrent GBM patients. Evidence shows that microglia is controlled by glioma cells resulting in their support for growth and thus, instead of destroying them they help by contributing to tumor progression. This maybe mediated through colony-stimulating factors, interleukin-6, TGF-β2 and monocyte chemotactic protein-1(MCP-1) that are being produced by glioma cells [Charles et al., 2011]. In turn, microglial cells support the survival, proliferation and invasion of glioma cells via secretion of factors such as EGF, VEGF and stress-inducible-protein-1 (STI1) [Alves et al., 2011].
45
ACCEPTED MANUSCRIPT Dendritic cell (antigen-presenting) vaccines are made from dendritic cells extracted from the patient, then exposed to the antigens of GBM cells and the same (now “primed”) cells are infused back into the patient. In turn, they activate the CD8+ (cytotoxic) T cells and present GBM
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antigen which is now being recognized by the host immune system. Tumor antigens that are being used are HER2, TRP2, Epha 2, GP100 and KI3ra [Lesniak et al., 2011]. Glioma stem cells contribute
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to resistance to chemoradiotherapy, thus introducing dendritic cells against these stem cells (using
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specific antigens such as CD133 and nestin) would be an important therapeutic target. In a nonrandomized phase II study, anti-EGFRvIII dendritic cell tumor vaccine addition to standard first line
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treatment in GBM patients with good performance status, when compared to a matched control
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group from MD Anderson, it resulted in an increase of median OS from 15 to 26 months and an increase in median PFS from 6.3 months to 14.2 months (hazard ration 2.4; P=o.o13 in favor of the vaccination group). The PFS-6 rate after vaccination was 67% (95% CI, 40-83%) and after diagnosis
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was 94% (95%, 67-99%, n=18). The development of antibodies or delayed type hypersensitivity had
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a significant effect on OS. When the tumor relapsed, EGFRvIII expression was lost in 82% (95% CI,
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48-97%). In subcategory analysis, outcomes were improved in both O-MGMT methylated and unmethylated patients. These results demonstrate that in EGFRvIII-positive GBM, outcomes are improved [Sampson et al., 2010]. Other treatment strategies include microglia as gene or factor therapeutic vectors into the central nervous system and glioma tumors. Examples include microglia carrying the LacZ gene [Sawada et al., 1998], inducible thymidine kinase gene or MRI contrast agents [Ribot et al., 2007] or biodegradable nano-vehicles carrying DNA or RNA silencer fragmants into the glioma tumor (Carbon nanotubes) [Zhao et al., 2011]. Microglial cell gene therapy through viral vectors of either adenovirus [Bhat et al., 2002] or lentivirus (the latter using an enhanced GFP gene) [Balcaitis et al., 2005] have also been tried. Intratumoral administration of oncolytic myxoma virus with rapamycin was another approach [Lun et al., 2012]. Although phase III data are lacking, preclinical and phaseI/II trial results, stongly state that immunotherapy is an area with promising results and offer a new weapon aginst this lethal tumor. 46
ACCEPTED MANUSCRIPT 3. Conclusion Research in GBM treatment is ongoing, vast, and rapidly evolving. However, even all this
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data and progression of molecular science it has not been able to battle effectively this tumor. No matter how many different targets are discovered and molecules to aim them are enginered, the
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end result is that we have made only a little progress forward in improving overall survival.
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However, as is seen in this review, every step in the way, new lessons drive us forward and small details help us bypass the presenting obstacles. New targets, novel antagonists, more effective drug
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penetration through the BBB and new methods of manipulating the immune response are all
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puzzles to be solved in the near future.
1.
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Conflict of Interest Statement: The authors declare that there are no conflicts of interest.
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ACCEPTED MANUSCRIPT maintenance therapy, in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation. Neuro Oncol, 15, 1405-12 281. Wick W., Weller M., Weiler M., Batchelor T., Yung A.W., Platten M. (2011). Pathway inhibition:
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ACCEPTED MANUSCRIPT an epidermal growth factor receptor mutant, EGFRvIII, in the brain. Mol Cancer Ther, 9(4), 929941. 292. Yin H., Zhou Y., Wen C., Zhou C., Zhang W., Hu X., et al. (2014). Curcumin sensitizes
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295. Zhang J., Stevens M.F. & Bradshaw T.D. (2012). Temozolomide: mechanisms of action, repair
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and resistance. Curr Mol Pharmacol, 5(1), 102-114.
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296. Zhang M., Herion T.W., Timke C., Han N., Hauser K., Weber K.J., et al., (2011). Trimodal gioblastoma treatment consisting of concurrent radiotherapy, temozolomide, and the novel TGF-β receptor kinase inhibitor LY2109761. Neoplasia, 13(6), 537-49. 297. Zhang M., Kleber S., Röhring M., Timke C., Han N., Tuettenberg J., et al. (2011). Blockade of TGF-β signaling by the TGFRβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res, 71(23), 7155-67. 298. Zhao D., Alizadeh D., Zhang L., Liu W., Farrukh O., Manuel E., et al. (2011). Carbon nanotubes enhance CpG uptake and potentiate antiglioma immunity. Clin Cancer Res, 17, 771-782. 299. Zou Y., Cao Y., Yue Z., Liu J. (2013). Gamma secretase inhibitor DAPT suppresses glioblastoma growth via uncoupling of tumor vessel density from vessel function. Clin Exp Med, 13(4), 271278.
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ACCEPTED MANUSCRIPT Table 1. Hereditary risk factors for GBM Gene
Associations
Neurofibromatosis type 1 (NF1)
NF1
Neurofibromas
Neurofibromatosis type 2 (NF2)
NF2
Schwannomas, ependymomas,
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Syndrome
meningiomas TP53
Sarcomas, breast cancer,
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Li-Fraumeni syndrome
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leukemia, adrenal cortex carcinoma, medulloblastomas
DNA mismatch
Colorectal adenomas,
cancer (HNPCC/Lynch syndrome), Turcot
repair (MSH2,
adenocarcinoma
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Hereditary non-polyposis colorectal
syndrome, Brain tumor-polyposis
MLH1, MSH6, PMS1, PMS2)
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syndrome (BTPS)
Multiple endocrine neoplasia type 1
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(MEN1), Werner syndrome
MEN1
Primary hyperparathyroidism, pancreatic endocrine tumors, pituitary adenomas
Nevoid basal cell carcinoma syndrome
PTC
Basal cell carcinomas,
(NBSCC), Gorlin-Gotz syndrome
CH
medulloblastomas, ovarian
Tuberous sclerosis complex (TSC)
fibromas TSC1, TSC2
Renal angiomyolipomas, retinal glial hamartomas, cardiac rhabdomyomas
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ACCEPTED MANUSCRIPT Table 2. Current treatment of newly diagnosed GBM# Maximal surgical resection plusa
i) RT plus concomitant and andjuvant TMZ ii)RT plus concomitant and adjuvant BCNU
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#: See text for dosages, RT: radiotherapy, TMZ: temozolomide, PCV: procarbazine, lomustine
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(CCNU), vincristine, BCNU: carmustine,
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ACCEPTED MANUSCRIPT Table 3. Therapeutic categories Chemotherapy
Alkylating drugs
Temozolomide Nitrosureas (carmustine,
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lomustine) Platinum Compounds
Irinotecan,
etoposide,
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cisplatin Vincristine (part of PCV
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Vinca Alkaloids
EGFR
ANG1005, Dichloroacetate, RTA 744
1) TKIs (erlotinib, gefitinib, afatinib, dacomitinib) 2) MTKIs (lapatinib, Vandetanib, Bay846)
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Targeted Therapy
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Other chemotherapeutic agents
regimen)
3) MAbs (cetuximab, MAb 806,
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nimotuzumab, panitumumab, AMG 595)
VEGFR
1) MTKIs (vatalanib, vandetanib, sunitinib, lenvatinib, pazopanib, cediranib, cabozatinibe, sorafenib) 2) MAbs (bevacizumab, ramucirumab, IMC-18F1 3) VEGF trap (Aflibercept)
PDGFR
1) MTKIs (Imatinib, dasatinib, nilotinib, tandutinib, bosutinib, sunitinib) 2) sTKI (Crenolanib) 3) MAbs (IMC-3G3, MEDI-575)
HGFR
1) MTKIs (cabozatinib, vandetanib,
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ACCEPTED MANUSCRIPT crizotinib, amuvatinib) 2) sTKI (SGX523) 3) MAbs (Rilotunumab, onartuzumab) 1) Cilengitide
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Integrins
2) Lenalidomide, Thalidomide* RAS/RAF/MEK/MAPK
1) FTIs (Tipifarnib, Lonafarnib, manumycin)
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Intracellular pathways
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2) RAF/MEK/MAPK(sorafenib,TLN-4601) PI3K/AKT/mTOR
1) PI3K (XL-147, Buparlisib)
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2) AKT (MK-2206, perifosine)
PKC
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3) mTOR (temsirolimus, sirolimus,
Tamoxifen, enzastaurin Cyclopamine, SEN450, Vismodegib, Erismodegib
NOTCH
Gamma Secretase Inhibitorss (RO4929097, MK-
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targets
4) PI3K/mTOR (XL-765, PI-103, PKI-587)
SHH/Gli1
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Other molecular
everolimus, ridaforolimus)
HDACs
0752, DAPT Vorinostat, panobinostat, romidepsin, trichostatin A)
Hsp
Tanespimycin
Proteasome
Bortezomib, marizomib, MG132
TGF-beta
Trabedersen, LY2109761
SRC, SFKs
dasatinib
Glutamate
Talampanel, riluzole
Topoisomerase
1) Topoisomerase 1 (captothecin,
inhibitors
irinotecan, NKTR-102) 2) Topoisomerase 2 (etoposide,
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ACCEPTED MANUSCRIPT teniposide) PARP-1
Iniparib, ABT-888
Other agents
C-150, aprepitant, artesunate, auranofin,
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disulfiram, nelfinavir, sertraline, captopril, ketoconazole, copper gluconate Cell surface molecule
L1/CAM antagonism
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Stem cell treatment
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targets
Vaccines
1) Peptide vaccines (Rindopepimut, ITK-1,
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Immunotherapy
Delta-24-RGD oncolytic adenovirus
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Viral vectors
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Dendritic cells
2) Gene-modified tumor vaccines
1) microglia as therapeutic vectors 2) viral vectors as gene therapy for microglia WP1193, WP1066
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JAK2/STAT3 pathway
HSPPV, Vitespen)
inhibitors
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S0163-7258(15)00096-0 doi: 10.1016/j.pharmthera.2015.05.005 JPT 6780
To appear in:
Pharmacology and Therapeutics
Please cite this article as: Alifieris, C. & Trafalis, D.T., Glioblastoma Multiforme: Pathogenesis and Treatment, Pharmacology and Therapeutics (2015), doi: 10.1016/j.pharmthera.2015.05.005
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ACCEPTED MANUSCRIPT P&T # 22714 Glioblastoma Multiforme: Pathogenesis and Treatment Constantinos Alifieris, Dimitrios T. Trafalis
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Laboratory of Pharmacology, Medical School, University of Athens, Greece
Corresponding Author:
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Assis. Professor Dimitrios Trafalis, MD, PhD
Lab. Of Pharmacology, Medical School, University of Athens
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75 Mikras Asias Str., 11527-Goudi, Athens, Greece (Building 16, 1st floor) Tel.: +30 210 746 2587; Fax: +30 210 746 2504
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Email: [email protected]
ACCEPTED MANUSCRIPT Abstract Each year, about 5-6 cases out of 100,000 people are diagnosed with primary malignant brain tumors, of which about 80% are malignant gliomas (MGs). Glioblastoma multiforme (GBM)
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accounts for more than half of MG cases. They are associated with high morbidity and mortality. Despite current multimodality treatment efforts including maximal surgical resection if feasible,
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followed by a combination of radiotherapy and/or chemotherapy, the median survival is short: only
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about 15 months. A deeper understanding of the pathogenesis of these tumors has presented opportunities for newer therapies to evolve and an expectation of better control of this disease.
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Lately, efforts have been made to investigate tumor resistance, which results from complex alternate signaling pathways, the existence of glioma stem-cells, the influence of the blood-brain
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barrier as well as the expression of 06-methylguanine-DNA methyltransferase. In this paper, we review up-to-date information on MGs treatment including current approaches, novel drug-
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future treatment perspectives.
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delivering strategies, molecular targeted agents and immunomodulative treatments, and discuss
Keywords: glioblastoma, treatment, review, pharmacology, targeted therapy, stem cell
Abbreviations
AKT, Protein kinase B; BBB, blood-brain barrier; BCNU, carmustin; CCNU, lomustin; c-MET, hepatocyte growth factor receptor; EGF(R), Epidermal growth factor (receptor); EGFRvIII, epidermal growth
factor
receptor
variant
III;
ERK,
Extracellular
signal-regulated
kinases;
FTI,
Farnesyltransferase inhibitor; GBM, Glioblastoma multiforme ; Gli1, Glioma-associated oncogene-1; HDAC, Histone deacetylase 1; HER2, Human epidermal growth factor receptor 2; HGF, Hepatocyte growth factor ; Hsp, heat-shock protein; IDH1, NADP+-dependent isocitrate dehydrogenase; MAb, Monoclonal antibody; MAPK, Mitogen-activated protein kinases; MG, Malignant glioma; MGMT, O6-methylguanine-DNA methyltransferase ; miRNA, micro ribonucleic acid; MRI, Magnetic resonance imaging; MTKI, Multitargeted tyrosine kinase inhibitor ; mTOR, Mammalian target of 2
ACCEPTED MANUSCRIPT rapamycin ; OS, overall survival; PARP-1, poly(ADP-ribose)polymerase-1; PCV, procarbazine, lomustine and vincristine; PDGF(R), Platelet-derived growth factor (receptor); PFS, Progression-free survival; PFS-6, Six-month progression-free survival; PI3K, Phosphotidylinositol 3-kinase ; PTEN,
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phosphatase and tensin homolog; RAF, Rapidly accelerated fibrosarcoma; RAS, Rat sarcoma; RT, Radiotherapy; SHH, Sonic hedgehog; STAT3, Signal transducer and activator of transcription 3; TKI,
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Tyrosine kinase inhibitor; TMZ, Temozolomide; TTP, time-to-progression;
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endothelial growth factor (receptor);
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Table of contents
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1. Introduction 2. Pathogenesis 3. Treatment
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5. References
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4. Conclusion
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VEGF(R), Vascular
ACCEPTED MANUSCRIPT 1. Introduction Each year, about 5-6 cases out of 100,000 people are diagnosed with primary malignant brain tumors, of which about 80% are malignant gliomas (MGs) [Stupp et al., 2010 b;
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Schwartzbaum et al, 2006]. Gliomas, the most common group of primary brain tumours, include astrocytomas, oligodendrogliomas and ependymomas. According to World Health Organization
anaplastic
oligodendroglioma,
anaplastic
oligoastrocytoma
and
anaplastic
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astrocytoma,
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(WHO) malignant gliomas are subcategorized into grade III/IV tumors such as anaplastic
ependymomas, as well as grade IV/IV tumors, as glioblastoma multiforme (GBM). The WHO grade is
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assigned based on certain pathological features, such as nuclear atypia, mitotic activity, vascular
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proliferation, necrosis, proliferative potential and features clinical course and treatment outcome [Louis et al., 2007]. Its incidence in the United States is estimated around 3:100,000 while more than 10,000 cases are diagnosed annually. It constitutes 45.2% of all malignant central nervous
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system (CNS) tumors, 80% of all primary malignant CNS tumors and approximately 54.4% of all
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malignant gliomas. Mean age at diagnosis is 64 years and it is 1.5 times more common in men than
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women and 2 times more common in whites compared to blacks [Ostrom et al., 2013]. The incidence has increased slightly over the past 20 years mostly due to improved radiologic diagnosis and especially in elderly [Fisher et al., 2007]. In terms of treatment, grade III tumors and GBM are grouped together and treated similarly. Clinically, patients with GBM may present with headaches, focal neurologic deficits, confusion, memory loss, personality changes or with seizures. Diagnosis and treatment response is suggested by magnetic resonance imaging (MRI) and the use of adjunct technology such as functional MRI, diffusion-weighted imaging, diffusion tensor imaging, dynamic contrast-enhanced MRI, perfusion imaging, proton magnetic resonance spectroscopy and positron-emission tomography [Wen et al., 2008]. Etiologically, there are known linked risk factors that lead to development of GBM Environmental risk factors include primarily exposure to therapeutic ionizing radiation and factors such as vinyl chloride or pesticides, smoking, petroleum refining or production work and 4
ACCEPTED MANUSCRIPT employment in synthetic rubber manufacturing [Wrensch et al., 2002]. Additional factors such as exposure to residential electromagnetic fields, formaldehyde, diagnostic irradiation and cell phones have not been proven to lead to GBM. However, regarding cell phone irradiation, a metanalysis
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released in 2007 did show increased incidence among people who used cell phones for at least 10 years and especially those who had mostly unilateral exposure [Hardell et al., 2007].
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Currently, maximal surgical resection plus radiotherapy plus concomitant and adjuvant
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temozolomide or carmustin wafers (Gliadel) is the standard of care in patients younger than 70 years old with newly diagnosed GBM. However, recurrence seems to be the rule despite standard
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care. Lately, attention has been given to understand the initial molecular pathogenesis of these
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tumors including alterations in cellular signal transduction pathways, the occurrence of resistance to therapy and to find methods to penetrate easier the natural blood-brain barrier (BBB). Despite these efforts to treat however, it remains an incurable disease and the prognosis falls in a poor
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survival range of 12-15 months (median 14.6 months) and a mean survival rate of only 3.3% at 2
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years and 1.2% at 3 years [Scott et al., 1998; Stupp et al., 2005].
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Glioma stem cells contribute to resistance to standard radiotherapy via preferential activation of DNA-damage-response pathways; and to standard chemotherapy via O6methylguanine-DNA methyltransferase (MGMT), the inhibition of apoptosis and the up-regulation of multidrug resistance genes [Dean et al., 2005]. Thus, current efforts are directed towards personalized treatment and through blocking prime signaling pathways in gliomagenesis, surpassing acquired resistance and penetration of BBB. In this article we review the current concepts as well as emerging advances in the treatment of GBM with an emphasis on chemotherapy and targeted agents.
2. Pathogenesis The ongoing research on the pathogenesis of malignant gliomas has given opportunities for newer therapies to evolve as well as promises for better control of the disease. Efforts are given to understand the development of tumor resistance [Dean et al., 2005; Furnari et al., 2007]. 5
ACCEPTED MANUSCRIPT A small subgroup (about 5%) of patients with gliomas, is associated with certain hereditary syndromes [Farrell et al., 2007] (table 1). All other patients with gliomas represent sporadic cases. An important aspect of the pathogenesis of gliomas is that malignant transformation results from
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the sequential accumulation of genetic alterations and abnormal regulation of growth factor signaling pathways. Aberrant proliferations is thus mediated via molecules such as vascular
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endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor
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(PDGF) and hepatocyte growth factor (HGF) and loss of phosphotensin analogue (PTEN). Downstream cascades in the growth signaling pathways (including PI3K/AKT) may be triggered
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[Wen et al., 2008]. Also, when those tumors recur, they often show progression to a higher
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histologic grade and thus, acquire a different name; this actually is a representation of progression along a classification scheme, the natural course of the disease, rather than a new disease [Louis, 2006]. Among the alterations that are most frequently seen in low-grade astrocytomas are
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mutations affecting p53 and overexpression of platelet-derived growth factor α (PDGF-α) and its
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receptor. The transition to a higher grade is associated to disruption of RB, p16/CDKNαA and 19q
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tumor suppressor genes [Louis, 2006].
GBM Clinical subtypes: GBM, is usually described in two different clinical forms, primary and secondary GBM [Kleihues et al., 1999]. Primary GBM, is the most common form (about 95%) and arises typically de novo, within 3-6 months, in older patients. Secondary GBM arises from prior low-grade astrocytomas (over 10-15 years) in younger patients. While primary and secondary forms show some molecular differences, the end result is pretty much the same since the same pathways are affected and respond similarly to current standard treatment. Primary GBM often has amplified, mutated epidermal-growth factor receptor (EGFR) which encodes altered EGFR (known as EGFRvIII) whereas secondary GBM has increased signaling through PDGF-A receptor. Both types of mutations lead to increased tyrosine kinase receptor (TKR) activity and consequently to activation of RAS and PI3K pathways. Again, primary GBM have commonly amplification of MDM2 gene (encodes for an inhibitor of p53), PTEN mutations and homozygous deletions of CDKN2A whereas secondary GBM usually has more prevalent p53 mutations, IDH1 mutations, MET 6
ACCEPTED MANUSCRIPT amplification and overexpression of PDGFRA. Finally, progression of low-grade glioma to high-grade is associated with inactivation of the retinoblastoma gene (RB1) and increased activity of human double minute 2 (HDM2) [Louis, 2006; Kleihues et al., 1999]. These aberrations primarily lead to
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abnormal regulation of two major cellular systems –the growth factor mediated signaling pathways and the cell cycle- and play a role in the increased cell proliferation, inhibition of apoptosis, invasion
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and angiogenesis [Louis ., 2006].
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Mutation in the nicotinamide adenine dinucleotide phosphate (NADP+)-dependent isocitrate dehydrogenase (IDH1) is conferring favorable prognostic value and prediction of response
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to temozolomide in GBM. However, patients with wild type IDH1 anaplastic astrocytomas exhibit
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worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of gliomas [Hartmann et al., 2010]. IDH1 mutations were found in less than 5% of primary GBM and characteristically in greater than 80% of secondary GBM. A recent
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meta-analysis study associated IDH1 mutations in GBM with improved OS [Cheng H., et al., 2013].
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GBM Molecular subtypes: Based on the growing understanding of molecular heterogeneity
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in GBM, the Cancer Genome Atlas (TCGA) divided this tumor in molecular subclasses termed classical, mesenchymal, proneural and neural types based on genetic alterations and expression profiles especially of PDGFRA, EGFR, NF1 and IDH1. Classical GBM is defined by aberrant EGFR amplification, astrocytic cell expression pattern and loss of chromosome 10 whereas IDH1, TP53 or NF1 mutations are not common. The mesenchymal subtype is defined by NF1 and PTEN mutations, a mesenchymal expression profile and less EGFR amplification than in other GBM types. The proneural subtype is characterized by PDGFRA focal amplification, TP53 and IDH1 mutations with an oligodenrocytic cell expression profile and younger presentation age. Finally, the neural subtype, is
characterized
by
normal
brain
tissue
gene
expression
profile
as
well
as
astrocytic/oligodendrocytic cell markers [Verhaak et al., 2010]. Primary and secondary GBM may be indistinguishable histologically but apparently differ in genetic and epigenetic profiles. Most GBM tumors with IDH1 mutations have the proneural gene expression pattern but only 30% of preneural GBM has the IDH1 mutation. Thus, IDH1 mutation is a more reliable and definitive molecular 7
ACCEPTED MANUSCRIPT diagnostic criterion of secondary GBM compared to clinical criteria. Secondary GBM (almost always the proneural subtype) is genetically more homogenous group regarding IDH1 mutation as compared to primary GBM [Ohgaki et al., 2013]. This heterogeneity of GBM profiles leads to
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different treatment efficacy among patients indicating that therapy must be personalized to target each patient’s alterations in the molecular level.
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Stem cells: The need for better understanding and managing patients with GBM, has led to
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the search for a defined cell type to target on. The discovery of multi-potent neural stem cells within the CNS which are capable of proliferation, self-renewal and differentiation, has led to the
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suggestion that a specific transformed CNS cell exists, which has the respective biological attributes
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of a somatic stem cell and may behave as a tumor initiating cell (TIC) [Facchino et al., 2011]. These stem cells express surface cluster designation markers such as CD133. Extensive studies, have led to the conclusion that those glioma stem cells promote angiogenesis by producing VEGF and can
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differentiate into pericytes, thus they create an optimal microenvironment for survival [Cheng L., et
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al., 2013].
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Mutations leading in gliomagenesis can occur in neural stem cells [Koso et al., 2012]. Possibly neural stem cells pass on mutations to downstream cells such as oligodendrocyte precursor cells (OPC), which are putative glioma cells. Introducing Neurofibromin-1 and p53 mutations into OPCs produces gliomagenesis in vitro (as occurs in Li-Fraumeni and Neurofibromatosis-1) [Liu et al., 2011]. Sonic hedgehog (SHH) signaling pathway, is presumed to be involved in the resistance (both chemotherapy and radiotherapy) and self renewal of cancer stem cells. Glioma-associated oncogene-1 (Gli1) –originally thought of being an oncogene involved in the pathogenesis of GBM- is part of SHH pathway. Normally, SHH acts via activation of the Gli1 transcription factor and thus participates in maintenance and proliferation of neural stem cells [Clement et al., 2007]. Cancer stem cells can be useful as targets by means of immunotherapy or inhibition of important specific pathways, as with signal transducer and activator of transcription 3 (STAT 3) or the activator bone marrow x-linked kinase (BMX) [Nduom et al., 2012]. 8
ACCEPTED MANUSCRIPT Targeting of stem cell signaling pathways is an evolving field which already shows some promising results. Innovative therapeutic responses as well as preventive approaches may be directed by this type of cells. Molecular GBM phenotype has broadened the list of targets in
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tumorgenic pathways. In GBM several tumor suppressor and oncogenic genes seem to be modulated by miRNAs thus delivery of genes or microRNAs (miRNA) can be another form of
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treatment [Møller et al., 2013].
3. Treatment
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Currently, the standard approach in managing GBM includes consideration of maximum
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surgical resection -considering that the entire tumor cannot be removed because GBM infiltrates surrounding tissue- radiation therapy (RT) and medical management/chemotherapy. It also includes symptomatic treatment of seizures, cerebral edema, infections, depression, cognitive
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dysfunction, fatigue and venous thromboembolism [Wen et al., 2006 a]. However, the analysis of
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symptom palliation is not in the scope of this review.
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The best therapeutic target is to pursuit a more individualized perspective. Thus, treatment depends on several factors such as the time of diagnosis, new onset or recurrence, the performance status and the age of the patient. Most GBM patients will follow a standard treatment after surgical resection consisting of external beam irradiation five times a week for six weeks, as well as oral temozolomide daily. Most patients will recur within 6.9 months of initial diagnosis. New agents or treatment administration techniques are typically initially tested first in the recurrent setting where there are some approved treatment alternatives. Table 2 depicts a summary of the current standard options for treatment of newly diagnosed GBM. In patients with either clinical or radiological progression, various treatment approaches have been assessed. As part of the multidisciplinary management of high grade gliomas, options include further surgery in selected patients, re-irradiation if also eligible, systemic chemotherapy, and clinical trial participation [Wen et al., 2008; Butowski et al., 2006]. As most patients are ineligible for re-operation or re-irradiation, clinical trial participation is the best option. Chemotherapy options (given as single agents) for high9
ACCEPTED MANUSCRIPT grade gliomas include carboplatin, irinotecan, carmustine (BCNU), etoposide and procarbazine, lomustine and vincristine (PCV) combination. Exciting preliminary data from clinical phase I/II trials support the development of epidermal growth factor receptor (EGFR) antagonists, mammalian
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target of rapamycin (mTOR) inhibitors, antiangioogenesis agents and other targeted inhibitors [Villano et al., 2009]. Even further, investigational approaches using convection enhanced delivery,
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stem cell treatment, immunotherapy and gene therapy based on recent pathogenetical discoveries,
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give excitement and promise for the future.
Chemotherapy for glioblastoma multiforme: Cytotoxic therapy for GBM has evolved, more
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due to the approval of temozolomide -an alkylating agent- for newly diagnosed GBM. Active agents
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include also the nitrosureas: carmustine (BCNU) and lomustine (CCNU), platinum agents, etoposide, irinotecan and PCV combination.
Temozolomide (TMZ) is a newer oral alkylating agent that has excellent penetration into
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the central nervous system. It is an imidazotetrazine derivative of dacarbazine. It has 100%
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bioavailability and promotes the methylation of the O6 position on guanine (N7-guanine and N3
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adenine). It was approved in 1999 for usage against malignant gliomas. Major toxicities include nausea and myelosuppression (often low platelet counts). Usually, an oral 5-HT3 antagonist is given 30-60 minutes prior to each dose. Dosage is usually started at 75mg/m2 daily concurrently with 6 weeks of regional radiotherapy to the surgical cavity and followed by 6 adjuvant cycles with maintenance dose at 150mg/m2 daily p.o. for 5 days for the first cycle and if well tolerated then scaled up to 200mg/m2/d for 5 days in 28-day cycles [Villano et al., 2009; Chinot et al., 2001]. Concurrent RT and TMZ results in a median overall survival (OS) of 14.6 months and 2-year survival rate of 26.5%. Temozolomide can be effective for recurrent GBM while its efficacy can be increased with metronomic rather than standard schedule as well as with high average daily dose (>100mg/m2) [Chen et al., 2013]. Patients with promoter MGMT methylation treated with RT/TMZ have a median survival of 23 months and 5- year OSof 14% versus RT alone (15 months and 5% respectively) [Stupp et al., 2009].
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ACCEPTED MANUSCRIPT The nitrosureas, carmustine (1,2 bis[2-chloreoethyl]-1-nitrosurea BCNU) and lomustine (CCNU), are two alkylating drugs used in the treatment of GBM and are associated with nausea, vomiting, rash, pulmonary fibrosis (rare) and a delayed myelosuppression and typically given in the
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dosage of 80mg/m2/d i.v. on days 1-3 every 6-8 weeks with radiation [Green et al., 1983]. Single agent BCNU is used most often as second line treatment in GBM that has progressed after TMZ.
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Carmustine biodegradable wafers (Gliadel) are an implantable depot form of BCNU that are placed
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in the cavity that is formed after resection of newly diagnosed or recurrent tumor. The wafers release topically BCNU for about 3 weeks. Although they are considered relatively safe they are not
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used by most centers because of delayed wound healing, intracranial edema, cerebrospinal fluid
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leakage, intracranial infection and seizures have been reported. Also, alterations in blood-brainbarrier make the interpretation of MRI unreliable [Nagpal et al., 2012]. Irinotecan, etoposide and cisplatin have been used in the treatment of GBM demonstrating
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modest efficacy as adjuvant chemotherapy. Since the approval of TMZ, they are mostly used as
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treatment after progression or recurrence. Since bavacizumab (see below), is increasingly being
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used in the recurrent setting, combinations of platinum compounds with bevacizumab have been used [Carrillo et al., 2012].
The PCV regimen combining procarbazine, lomustine (CCNU) and vincristine is commonly used in the treatment of anaplastic astrocytomas and oligodendrogliomas. Procarbazine is also a monoamine oxidase inhibitor and is associated with allergies and hypertensive crisis especially in response to certain foods such as those containing tyramine –aged cheese, nuts, red wine- which patients are advised to avoid consuming. Vincristine is a vinca alkaloid (binds to tubulin), is associated with a syndrome of jaw pain after the first dose and maybe peripheral neuropathy. This combination is usually given as CCNU 110mg/m2 p.o. on day 1, procarbazine 60 mg/m2/d p.o. on days 8-21 and vincristine 1.4 mg/m2 (maximum dose 2 mg) i.v. on days 8 and 29, repeated every 6 weeks [Glass et al., 1992]. PCV in recurrent GBM has not shown significant results [Schmidt et al., 2006].
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ACCEPTED MANUSCRIPT Investigational cytotoxic agents: GRN1005 (ANG1005) is a novel agent that consists of three paclitaxel molecules linked to a novel peptide –angiopep- that allows it to be transported across the blood-brain barrier through the low-density lipoprotein-related protein 1 receptor. In a phase I
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study, prodrug GRN1005 was tried in patients with recurrent or progressive malignant gliomas and it was fairly well tolerated while showed antitumor activity. It penetrated the blood-brain barrier
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[Drappatz et al., 2013]. Dichloroacetate (DCA) is an inhibitor of the mitochondrial pyruvate
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dehydrogenase kinase induces apoptosis in vitro and in vivo of GBM cell lines [Michelakis et al., 2012]. A phase II study evaluates DCA in patients with GBM and results are pending
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(NCT00540176). RTA 744 is a close chemical analogue of doxorubicin but is more effective in
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crossing the blood brain barrier and is able to achieve high concentrations in the CNS tumor tissue in animal models. A phase I study of RTA 744 in patients with recurrent high-grade gliomas has been completed but results have not been published yet (NCT00526812).
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Resistance to chemotherapy and radiotherapy: Many GBMs have intrinsic or acquired
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resistance to chemotherapy. MGMT gene promoter methylation and thus silencing and
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downregulation of the gene is an important mechanism of resistance to temozolomide treatment in GBM. MGMT is a repair gene that removes alkyl groups from the O6 position of guanine and in this way it alleviates the effects of alkylating drugs (temozolomide or the nitrosureas) [Hegi et al., 2005; Esteller et al., 2000]. Methylation of MGMT is found in 30-60% of GBM cases and is associated with a favorable outcome if treated with alkylating agents [Hegi et al., 2005]. A common mechanism that confers this resistance is mediated by MGMT. If the promoter of this gene is methylated, glioma cells are more sensitive to temozolomide. One way of surpassing this resistance is with dose-dense (days 1-21 every 28 days) or dose-intense regimens [Clarke et al., 2009], or by direct inhibition of MGMT via O6-benzylguanine in combination with TMZ [Quinn et al., 2009]. A second mechanism that gives resistant properties to these tumors is that of poly(ADP-ribose)polymerase-1 (PARP-1). PARP-1 is a critical base-excision-repair gene and that when disrupted results in persistence of potentially lethal N7- and N3- purine lesions contributing to TMZ cytotoxicity especially when O6methylguanine adducts are repaired or tolerated. PARP-1 small molecule inhibitors such as BSI-201 12
ACCEPTED MANUSCRIPT (iniparib) and ABT-888 are promising either alone or in combination with TMZ [Wen et al., 2008, Zhang et al., 2012]. In preclinical trials, inhibition of another target important to base-excisionrepair, abasic (AP) endonocluease-1 (APE-1) shows potentiation of TMZ activity [Zhang et al., 2012].
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There is evidence that glioma stem cells contribute to GBM chemoresistance. Stem cells from highly chemotherapy resistant grade IV gliomas show expression of multidrug resistance
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protein-1 (MRP1) transporters and grade II gliomas show expression of P-glycoprotein (Pgp) [De
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faria et al., 2008]. Moreover, cancer stem cells express MDR1 at higher levels than differentiated cancer cells, favoring resistance to chemotherapy agents such as temozolomide, etoposide,
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paclitaxel and carboplatin in undifferentiated cells and thus serving as an adequate reasoning for
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this high frequency of tumor recurrence with existing treatment [Liu et al., 2005]. TMZ also results in induction of EGFRvIII and EGFR expansion, which can be blunted by the use of EGFR inhibitors such as erlotinib [Munoz et al., 2014]. Medication such as verapamil and cyclosporine A that inhibit
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[Linnet et al., 2008].
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p-glycoprotein in vitro, can increase brain retention of chemotherapy drugs such as vincristine
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Drug molecular targets in glioblastoma multiforme: The continuously evolving field of understanding the molecular pathogenesis of GBM prompted to a more rational use of targeted molecular therapies. Inhibitors that target receptor tyrosine kinases (EGF, PDGF, VEGF, HGF, IGF receptors) and signal transduction inhibitors targeting mTOR, AKT/PI3K and farnesyltransferase are being investigated. Unfortunatelly, up till now, monotherapy with these agents show disappointing results or at most mild-modest efficacy with response that is between 0 to 15% and are unable to prolong the progression free survival [Sathornsumetee et al., 2007]. Because highly targeted agents were not being successful, the current approach is combined inhibition of multiple molecular targets within the same pathway (proximal and distal) or between separate-parallel pathways but with the cost of increased toxicity. Nevertheless, no combination therapy has shown enhanced clinical benefit over single agents [Wilson et al., 2014] Tyrosine kinase associated receptors serve in the transmission of signals from extracellular ligands to cell nucleus and share some common pathway mechanisms and intracellular signaling. 13
ACCEPTED MANUSCRIPT They are composed of a ligand-binding extracellular domain, a lipophilic transmembrane domain and an intracellular domain containing a catalytic site. In the absence of their associated ligand, tyrosine kinase receptors remain unphosphorylated, monomeric and inactive. After the appropriate
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ligand binds its associated receptor, the receptors undergo dimerization and then autophosphorylation in which the kinase domain of one receptor phosphorylates one or more
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intracellular tyrosine residues on the second receptor. Those phosphotyrosine residues in turn,
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become binding sites and recruit adaptor proteins and activate downstream effect on molecules which initiate specific signaling cascades with end result the regulation of gene transcription.
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Adaptor proteins include growth factor receptor-bound-2/son-of-sevenless (Grb2)/(SOS) effect on
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serine/threonine kinases such as RAS, phosphatidyloinositide-3-kinase (PI3K) and phospholipase C (PLC). Negative kinase regulators include PTEN in the PI3K pathway. Important intracellular mediators in oncogenic biochemical pathways include RAF-MEK-ERK, AKT and mTOR.
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The alterations in gene synthesis result in cell growth, proliferation, migration, angiogenesis
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and apoptosis. Within tumor cells, dysregulation can occur with various mechanisms mainly with
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overexpression or mutations of receptors and intracellular domains, activation of biomolecules, inactivating mutations of their negative regulators and lead to constitutive activation of signaling pathways and uncontrolled cellular survival, proliferation and invasion [Arora et al., 2005]. C-Kit is another receptor tyrosine kinase that acts similarly to EGFR and PDGFR and is found to be overexpressed in GBM. Binding of ligands and specifically the stem cell factor to c-Kit, results in receptor dimerization and activation of several transduction pathways including Akt, Src family kinases, PI3K, Ras/MAPK and PLC-γ. [Arora et al., 2005]. Angiogenic pathway inhibition: GBM is a highly vascularized malignancy with marked angiogenesis and high expression of VEGF which is also needed for stem cells to create an optimal functional environment. Antiangiogenic agents, a group of continuously evolving targeted therapeutics, have demonstrated promising results in many trials [Onishi et al., 2013]. Older agents like thalidomide and newer anti-VEGF or anti-VEGFR therapies, as well as anti-HGF and anti-avβ5 integrin molecules are included. VEGF is a member of the platelet-derived growth factor family. 14
ACCEPTED MANUSCRIPT There are numerous ligands for VEGF receptors (VEGFRs) including VEGF-A to –E and placenta growth factor. VEGFRs are expressed on vascular endothelial cells [Ferrara., 2005]. Ligand binding to VEGFR-1 (Fms-like tyrosine kinase 1 or Flt-1) induces endothelial cell migration, where as binding
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to VEGFR-2 (kinase insert domain-containing receptor or KDR) stimulates endothelial cell proliferation, increases vascular permeability (this probably accounts for the vasogenic edema of
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GBM seen on MRIs), increases the expression of proangiogenic factors (matrix metalloproteinase-1,
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urokinase-type plasminogen activator and it’s receptor, plasminogen activator inhibitor-1), has antiapoptotic effects and VEGFR-2 activates primarily the tyrosine kinase domains once ligands
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attach. Binding to VEGFR-3 (Flt-4) leads to lymphangiogenesis. Several factors may upregulate VEGF
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expression including hypoxia (the most important factor in tumor cells), HGF, PDGF, FGF, EGF, TNF, TGF-β, IL-1, c-KIT, the PI3K-Akt and Ras-MAPK pathways, acidosis, wound healing, endometriosis and embryogenesis [Ferrara., 2005]. Neoplasms such as GBM, require their own vascular supply to
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maintain survival beyond the size of 2 mm. The early small tumor extensions can receive the
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needed vascular supply from the glial vasculature by “co-opting” along the capillaries. To achieve
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this, angiogenesis must take place [Jain et al., 2007]. However, blocking the VEGF pathway provides means of blocking the new vessels with high permeability (“leaky vessels”) and thus decreasing hypoxia in the tumor and consequently they disrupt a vital mechanism of survival in glioma stem cells, they decrease neoangiogenesis, hypoxia, vascular permeability (and vasogenic edema) and increase chemotherapy delivery and radiosensitivity [Jain et al., 2007; Bao et al., 2006]. Inhibitors of VEGF signaling pathway include small molecule tyrosine inhibitors, MAbs and VEGF binding agents. EGFR is the most frequent amplified gene seen in malignant gliomas. The EGFR is one of four tyrosine kinase receptors within the ErbB receptor family, that is ErbB1 (EGFR/HER1), ErbB2 (HER2/neu), ErbB3 (HER3) and ErbB4 (HER4). Activation of these receptors result in turn in activation of multiple downstream signaling pathways as fore-mentioned, including the Ras/Raf/MEK/ERK1/2-mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3’-kinase(PI3K)/Akt/mTOR pathway and the signal transducer and activator of transcription 15
ACCEPTED MANUSCRIPT pathways (STAT 3 and 5). Ligands for these receptors include EGF and transforming growth factor α (TGF-α). These pathways affect cell proliferation, migration, differentiation, inhibition of apoptosis and upreguletion of VEGF expression and thus increased angiogenesis [Mendelsohn et al., 2006].
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Activation of EGFR can be due to: a) increased expression or activity of EGFR ligands or cofactors, b) EGFR gene amplification or increase in translation (50-60% of GBM cases), and c) activating
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mutations of EGFR, like the EGFRvIII mutant (mediates radioresistance and it confers a more
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malignant potential than the wild type receptor, found in 50-60% of GBMs) [Ye et al., 2012]. EGFR signaling alterations are associated with worse clinical prognosis, decreased OS and gliomagenesis
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[Shinojima et al., 2003]. Currently, EGFR inhibition has been tried by using small molecule tyrosine
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kinase inhibitors, monoclonal antibodies, peptide vaccines, antisense oligonucleotides and immunotoxin conjugates.
Platelet-derived growth factor (PDGF) and its receptor (PDGFR) are also commonly
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overactive in about 30% of GBM cases. The PDGF family consists of four members, PDGF-A through
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–D which signal through the alpha and beta PDGFR (PDGFR-α; PDGFR-β). Activation of PDGFR
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triggers multiple intracellular signaling pathways, much like the EGFR. They include PI3K, MAPK, Jak family kinase, Src family kinase and phospholipace C-gamma (PLC-γ) [Joensuu et al., 2005]. Thus, it promotes tumor growth through autocrine stimulation, angiogenesis through paracrine effects on reciprocal endothelial cells and affects tumor fibroblast regulation (which in turn leads to transvascular transport of drugs through alterations in intratumoral pressures) [Ostman et al., 2004]. PDGF expression (but not PDGFR-α) is associated with the tumor grade and proliferative activity of oligodendrogliomas [Majumdar et al., 2009]. PDGF-C has been shown to induce the maturation of blood vessels in GBM experimental models and attenuate the response to anti-VEGF treatment [di Tomaso et al., 2009]. Drugs that block the PDGFR include tyrosine kinase inhibitors and MAbs. Hepatocyte growth factor (HGF) or scatter factor activates the EGF, VEGF and HGF pathways. When it binds to the c-MET receptor, it activates intracellular signaling cascades similar to those triggered by the EGF and PDGF receptors such as MAPK, PI3K-Akt, V-Src and STAT. C-Met 16
ACCEPTED MANUSCRIPT signaling has been associated with gliomagenesis, increased cell growth, scattering and motility, invasion, resistance to apoptosis and angiogenesis [Sierra et al., 2011]. It has also been postulated that c-MET activation may bypass EGFR tyrosine kinase inhibition in sensitive cells by either
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autophosphorylation of c-MET or transphosphorylation of other ErbB receptors (‘cross talk’) thus acting as a mechanism of resistance to anti-EGFR treatment [Sierra et al., 2011]. HGF autocrine
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GBM may predict sensitivity of GBM cells to c-MET inhibitors and serum HGF levels may be serve as
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biomarker for the presence of autocrine tumors and responsiveness to c-Met inhibition therapy [Xie et al., 2012]. Also, targeting of the c-Met pathway is found to potentiate GBM rensposiveness
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to gamma irradiation [Lal et al., 2005]. Preclinical evidence have demonstrated that PTEN loss
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amplifies c-Met induced GBM malignancy and it is suggested that trials of the combination of antiHGF blocking plus PTEN restoration or mTOR inhibition should be carried out [Li et al., 2009]. Elevated serum HGF may be associated with poor response and a shorter PFS in patients with GBM
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undergoing first-line RT [Liang et al., 2014].
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Most important intacellular effector molecules in the pathogenesis of malignant gliomas
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are biochemically active serine/threonine kinases. These include PI3K, RAS, PLC etc. and either activation of them or inactivation of their negative regulators lead to excessive phosphorylation in the intracellular signal pathways and thus contribute to malignancy. RAS-RAF-MEK-MAPK pathway: The Ras gene superfamily encodes small GTP (guanine triphosphate)-binding proteins (GBPs) which are found in the inner cell membrane and regulate cellular functions, including cytoskeletal organization, protein trafficking, cellular differentiation and proliferation as well as secretion of angiogenetic molecules. Ras mutations are not common in malignant gliomas but they rather show increased Ras activity due to amplification or mutation of upstream growth factor receptors [Knobbe et al., 2004]. When Ras is triggered by either EGFR or PDGFR activation or through independent pathway alterations, the mitogenic signal through the mitogen activated protein kinase (MAPK also known as ERK) and phosphatidylinositol 3-kinase (PI3K) pathways are initiated. However, translocation of Ras to the cell membrane for activation requires a post-translational alteration which is catalyzed by farnesyltransferase. Farnesylation is 17
ACCEPTED MANUSCRIPT the rate-limiting step in RAS maturation although not unique for Ras [Sebti et al., 2004]. Downstream of Ras, is the pathway Raf-Mek-MAPK pathway. Activation of MAPK is associated with poor outcome in GBM [Pelloski et al., 2006].
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Phosphotidylinositol 3-kinase (PI3K) /AKT/mTOR (mammalian target of rapamycin) pathway is a group of serine/threonine kinases. PI3K can be activated by other tyrosine kinase receptors
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(EGFR, PDGFR, c-Met), active Ras or integrins. It regulates cellular mechanisms and when altered
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can lead to decrease of apoptosis, increase in cell growth and cell proliferation. It is a poor prognostic factor in patients with malignant gliomas [Chakravanti et al., 2004]. AKT (also known as
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protein kinase B), is a downstream effector of PI3K -activated when phosphorylated- and leads to
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the same cellular results. mTOR is downstreamed from AKT and can be activated by RAS pathway also. At least 2 separate mTOR complexes exist. Each complex is composed of a common regulatory subunit, the target of rapamycin (TOR) and a downstream-substrate-defining subunit. The latter
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includes raptor subunit (in mTOR-complex-1, mTORC1) and rictor subunit (in mTOR-complex-2,
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mTORC2). Rapamycin only inhibits mTORC1. The raptor subunit of mTORC1 regulates protein
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transcription which involves 4E-BP1 (initiation factor 43 binding protein-1) and p70s6K (ribosomal S6 kinase). The most important negative regulator of the PI3K/Akt/mTOR pathway seems to be PTEN (phosphate and tensin homologue) [Sheppard et al., 2012]. In GBM the PI3K/AKT/mTOR pathway is active in about 70% of cases and it seems to regulate the proliferation and tumorigenic potential in GBM cancer stem cells. Rapamycin seems to inhibit this potential in vitro but not in vivo, hence it may be of limited value as monotherapy in GBM [Mendiburu-Eliçabe et al., 2013]. Protein kinase C (PKC) is another serine/threonine kinase that regulates glioma cell proliferation, angiogenesis and invasion. It is activated by other tyrosine kinase receptors and Gprotein coupled receptors. PKC-β mediates VEGFR2 signalling through its associated MEK/MAPK pathway [Kreisl et al., 2010]. Apart from conferring resistance to chemo- and radio-therapy and increase in survival of stem cells the Sonic hedgehog/Gli1 (SHH/Gli1) pathway seems to also act in migration and glioma cell invasion [Wang et al., 2010]. 18
ACCEPTED MANUSCRIPT GBM is characterized by the presence of increased growth factor signaling, hypoxia, angiogenesis and the presence of brain glioma cancer-stem-cells, conditions in which Notch signaling could prove to be a key. Specifically, regarding stem-cells there is evidence that by
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blocking this pathway in combination with other targeted treatments, a better control of these neoplasms could be achieved [Stockhausen et al., 2012]. Gamma secretases, mostly known for their
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role in the final step of processing amyloid precursor protein in Alzheimer’s disease through the
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generation of amyloid-beta peptides, also play a key role in Notch signaling pathway[Stockhausen et al., 2012; Lin et al., 2010].
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The integrins are heterodimeric transmembrane cell adhesion molecules and receptors that
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bind multiple extracellular ligands (e.g. matrix proteins like collagen, laminins, vitronectins and fibronectins). This binding activates integrins and thus regulates tumor cell invasion and metastasis, migration, proliferation, angiogenesis and survival. The regulation of these effects is mediated via
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downstream signaling pathways that signal in parallel to other pathways like EGFR, VEGF and
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PDGFR. There are at least 24 integrin types and are widely expressed throughout the vasculature.
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The integrins alphaVbeta3 (αVβ3) and alphaVbeta5 (αVβ5) are highly expressed in malignant glioma tumor cells and on endothelial cells at tumor peripheral vessels. Peptide-based integrin inhibitors as well as monoclonal antibodies are being investigated as means of inhibiting this cellular mechanism. Integrin inhibitors decrease tumor hypoxia [Tabatabai et al., 2010]. Integrin overexpression has been found in glioma stem cell microenvironment [Lathia et al., 2010]. Molecular pathway & kinase inhibitors: EGFR tyrosine kinase inhibitors (TKIs) are small molecules that bind to the ATP-binding site on the tyrosine kinase domain of the receptor and inhibit the catalytic activity of the kinase. They can also inhibit fusion tyrosine kinases by blocking their dimerization. Furthermore, they interact with VEGFR and other human epidermal receptors [Yarden et al., 2001]. Examples include the competitive antagonists, erlotinib and gefitinib (administered orally), as well as the newer irreversible antagonists afatinib and dacomitinib. Erlotinib in two separate phase II trials with patients with recurrent GBM, showed that it is ineffective as monotherapy showing progression free survival at 6 months (PFS-6) in 3% of patients 19
ACCEPTED MANUSCRIPT and a median PFS of 2 months [Raizer et al., 2012] and PFS-6 in 11.4% vs 24% of control (treated with TMZ or carmustine) [van den Bent et al., 2009]. Gefitinib, in a phase II study with recurrent GBM patients, demonstrated event-free survival (EFS) of 13.2% at 6 months [Rich et al., 2004].
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Systemic toxicity has been used as a way to predict the clinical efficacy of treatment (e.g, rash, diarrhea). For example in a study, diarrhea from gefitinib treatment was associated with better
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OSwhereas EGFR expression (either EGFRvIII or wild-type) did not correlate with prediction of OS
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[Rich et al., 2005]. On the other hand, co-expression of EGFRvIII and PTEN in GBM seems to predict a better response to EGFR inhibition (fifty times more likely) [Mellinhoff et al., 2005]. In a phase II
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trial with patients with recurrent GBM given afatinib alone, showed PFS-6 in 3% of patients but
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possibly was more effective in patients with EGFRvIII mutations [Eisenstat et al., 2011]. A study of afatinib and radiotherapy with or without temozolomide is under way (NCT00977431). Dacomitinib (PF-299804) is a new pan-HER irreversible inhibitor that shows enhanced action against glioma-
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specific domain IV EGFR cysteine mutations [Greenall et al., 2014] and is currently been evaluated
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in two phase II studies, one with GBM patients with EGFR amplification or EGFRvIII expression
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(NCT01520870) and another in seeking of efficacy in recurrent/relapsed GBM (NCT01112527). As a conclusion, erlotinib appears to be more effective against malignant gliomas than gefitinib. Higher levels of EGFR expression can be associated with better response to erlotinib [Haas-Kogan, et al., 2005 a]. Although, EGFR has clearly a great and important role in the pathogenesis of high grade gliomas, trials up to date with EGFR inhibitors failed to show promising results. Explanations may be the acquisition of new resistance mutations and/or inability to cross effectively the blood brain barrier (BBB). Also, proximal block of the EGFR pathway, may be overridden by overactive distal effectors (high pAKT) [Haas-Kogan, et al., 2005 b]. Tyrosine kinase inhibitors have been developed to block the VEGF pathway. However, although they are many and primarily antagonize angiogenesis they also have mixed tyrosine kinase blocking effects. Inhibitors that have primarily VEGFR blocking effects include vatalanib, vandetanib, sunitinib, pazopanib, cediranib and cabozantinibe. They will be discussed below.
20
ACCEPTED MANUSCRIPT As in VEGFR pathway, small molecule inhibitors have been developed against PDGFR. However, they have mixed effects and are not selective for PDGFR. Examples of inhibitors with primarily actions against PDGFR include imatinib, dasatinib, nilotinib and tandutinib. They will be
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discussed below. Crenolanib (CP-868,596), a novel oral selective and potent PDGFR inhibitor, is currently being evaluated in a phase II study of adult malignant gliomas (NCT01229644) and in a
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phase I study of pediatric/young adult recurrent high grade gliomas (NCT01393912).
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Small molecule inhibitors targeting c-MET pathway have been developed but not all of them show selectivity for the c-MET receptor. SGX523 is a highly selective oral c-MET inhibitor that
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has been shown to be effective in vitro and in vivo against GBM cell lines. Although two separate
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phase I studies with SGX523 were prematurely terminated (NCT00606879, NCT00607399), it may still serve as a guide of investigating the role of MET in cancer until further clinical evaluation [Buchanan et al., 2009; Guessous et al., 2010].
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Farnesyltransferase inhibitors (FTIs) have been tried in the treatment of malignant gliomas.
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Tipifarnib (R115777), in a phase II trial exhibited modest efficacy as monotherapy in patients with
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recurrent malignant gliomas. PFS-6 was 11.9% for GBM patients. Toxicity was tolerated well except the subset of patients that received enzyme inducing antiepileptic drugs which presented an increased hematological toxicity [Cloughesy et al., 2006]. R115777 administered before RT in patients with newly diagnosed GBM and residual enhancing disease did not lead to any measurable benefit [Lustig et al., 2008; Nghiempu et al., 2011]. The R115777 plus RT combination with or without TMZ, in newly diagnosed GBM seems to be well tolerated [Nghiempu et al., 2011]. Another phase I/II trial of R115777 with RT in patients with newly diagnosed GBM produced a median OSof 60.4 weeks but time to progression (TTP) was only 18.1 weeks where both FGFR1 and αvβ3 integrin expressions being independent bad prognostic factors [Ducassou et al., 2013]. A phase I/II trial of the combination of sorafenib combined with erlotinib, tipifanib or temsirolimus in recurrent GBM has been completed and results are pending (NCT00335764). Lonafarnib (SCH66336) against U87 GBM cell lines improved activity of TMZ/RT [Chaponis et al., 2011]. In a phase I study on Ionafarnib with TMZ in malignant glioma patients demonstrated dose limiting hepatic, gastrointestinal 21
ACCEPTED MANUSCRIPT (vomiting, diarrhea, anorexia), renal, thrombotic and constitutional toxicities (headaches) [Desjardins et al., 2011]. In progressing GBM, intensifying TMZ treatment and adding lonafarnib a PFS-6 of 33% and partial response of 27% in previously non-responding patients was achieved
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[Gilbert et al., 2006]. In another phase I/Ib study of lonafarnib and dose-dense schedule of TMZ in recurrent/TMZ refractory GBM, toxicity was acceptable and PFS-6 was 38% and median survival
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13.7 months [Yust-Katz et al., 2013]. Manumycin, a FTI, has been found to induce reactive osxygen
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species (ROS) and glioma cell apoptosis, inhibits STAT3 and telomerase activity [Dixit et al., 2009] as wall as targets the IL1β-Ras-HIF-1α axis [Sharma et al., 2012].
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TLN-4601, a novel Ras-MAPK inhibitor, has been studied on first progression status of GBM
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in a phase II study. Although it was well tolerated (except two patients who discontinued the medication due to toxicities) at the proposed dosage, it was largely ineffective as monotherapy
It is discussed under MTKI section.
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[Mason et al., 2012]. Sorafenib, is an oral MTKI that also targets B-Raf and C-Raf [Guan et al., 2011].
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Selective PI3K inhibitors include XL-147, buparlisib and BKM120. XL147 (SAR245408) is a
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selective and reversible class I PI3K inhibitor that has been used in an exploratory trial in patients with recurrent GBM who were surgical candidates (NCT01240460). Buparlisib (NVP-BKM120) is a selective PI3K inhibitor demonstrated antitumor activity in U87 glioma cells [Koul et al., 2012]. BKM120 is currently under investigation in a phase II study with recurrent GBM patients (NCT01339052), a phase I dose escalation trial along with TMZ/RT in newly diagnosed GBM (NCT01473901) and a phase I/II study in combination with bevacizumab in patients with relapsed/recurrent GBM (NCT01349660). GBM patients who carry mutant PIK3R1 alleles may benefit from targeted inhibition of AKT since signaling through PI3K promotes tumorigenesis [Quayle et al., 2012]. MK-2206, an allosteric AKT inhibitor, is currently undergoing phase I/II trials [Hirai et al., 2010]. Perifosine (KRX-0401) is a novel Akt inhibitor. It has been evidenced to inhibit multiple intracellular signaling pathways in glial progenitors and cooperates with TMZ to arrest glioma cell proliferation in vivo [Momota et al., 2005]. It does not seem to be able to enhance the radiosensitivity of human glioma cells [De la Pena 22
ACCEPTED MANUSCRIPT et al., 2006]. Also, perifosine in combination with temsirolimus shows synergism in inducing apoptosis and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine GBM cells [Pitter et al., 2011]. Currently an ongoing phase I/II study seeks to investigate the combination
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of temsirolimus plus perifosine in recurrent or progressive malignant gliomas (NCT01051557) and a phase II study investigates perifosine monotherapy in recurrent/progressive malignant gliomas
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(NCT00590954).
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mTOR inhibitors used in malignant gliomas are either selective (e.g. temsirolimus, sirolimus, everolimus, ridaforolimus) or dual PI3k/mTOR inhibitors (XL-765, PI-103, PKI-587). Temsirolimus
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(CCI-779) is a specific mTOR inhibitor. In a phase II trial of temsirolimus against recurrent GBM,
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radiographic response in 36% of patients, PFS-6 7.8%, median OS4.4 months, median TTP 2.3 months (responders: 5.4 months vs non-responders: 1.9 months) were observed. It was generally well tolerated [Galanis et al., 2005]. In a second phase II study of temsirolimus on recurrent GBM
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no efficacy was demonstrated, though 50% of patients were initially stable. Once again the toxicity
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profile was well tolerated [Chang et al., 2005]. However, temsirolimus in combination with TMZ/RT
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showed increased risk of infectious complications [Sarkaria et al., 2010]. Various combinations have been either in ongoing trials or in completed ones. Sirolimus (rapamycin, AY-22989, WY-090217), is a selective mTOR inhibitor. It was found to achieve a partial radiographic response in 6% and stable disease in 38% of patients when combined with gefitinib, in a phase I study. Dose limiting toxicity included mucositis, diarrhea, thrombocytopenia and hypertriglyceridemia [Reardon et al., 2006]. In a phase II trial, combination of elrotinib and sirolimus in patients with recurrent GBM was ineffective and demonstrated a dismal PFS-6 of 3.1% but was generally well tolerated [Reardon et al., 2010]. Everolimus (RAD001) is an mTOR inhibitor of FKBP12. In a phase I trial of everolimus and temozolomide in combination with radiotherapy was found to be well tolerated in newly diagnosed GBM patients [Sarkaria et al., 2011]. A phase II study of concurrent TMZ/RT/bevacizumab followed by bevacizumab/everolimus following surgical resection in newly diagnosed GBM patients, demonstrated PFS of 11.3 months and median OSof 13.9 months. This efficient regimen was associated with everolimus related dose limiting toxicities like fatigue, pneumonitis and stomatitis. 23
ACCEPTED MANUSCRIPT Bevacizumab related side-effects were also observed. However, the PFS is favorable to standard TMZ/RT historical reports [Hainsworth et al., 2012]. Ridaforolimus (Deferolimus, AP23573, MK8669) is a selective mTOR inhibitor. In a phase II study on progressive or recurrent malignant
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gliomas, ridaforolimus given perisurgically was found to be able to cross the blood-brain barrier and with histological evidence it achieved mTOR inhibition, with an expected, well tolerated and no
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dose-limiting toxicity profile [Reardon, 2012 b]. A phase I safety study of ridaforolimus is completed
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in progressive/recurrent gliomas (NCT00087451). XL765 is a dual inhibitor of PI3K/mTOR that has been studied in vivo and in vitro against GBM cells and demonstrated efficacy both alone and in
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combination with TMZ [Prasad et al., 2011]. Two ongoing phase I studies use XL765, (a) in
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combination with TMZ with or without RT in malignant gliomas (NCT00704080) and (b) along with XL147 in surgical candidates with recurrent GBM (NCT01240460). PI-103 is a potent, cell permeable, ATP-competitive class I PI3K inhibitor and mTORC1/2 inhibitor. It was found to be
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efficient against malignant glioma xenografts [Fan et al., 2006]. PKI-587 (PF-05212384) is a dual
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PI3K/mTOR inhibitor that was found to be effective against glioma U87 cell lines [Mallon et al.,
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2011] and is now investigated in a safety phase I study. Two novel ATP-competitive mTOR inhibitors CC214-1 and CC214-2 suppress rapamycin resistant mTORC1 signalling, block mTORC2 especially in EGFRvIII activated GBMs. It also seems that autophagy helps cancer cells to overcome mTOR inhibition [Gini et al., 2013].
Enzastaurin (LY317615), a potent PKC inhibitor has been trialed against malignant gliomas. A phase I/II study of enzastaurin monotherapy in malignant gliomas demonstrated 25% radiographic response with PFS-6 of 7% (in GBM) and of 6% (in anaplastic glioma). Glycogen synthase kinase-3 in peripheral blood mononuclear cells was identified as a potential marker for drug activity [Kreisl et al., 2010]. However, a later phase III study comparing enzastaurin with lomustine in recurrent intracranial GBM did not show superior efficacy although it was less hematologically toxic [Wick et al., 2010]. A phase II study of TMZ plus enzastaurin during and after RT in newly diagnosed GBM was well tolerated and exhibited a median OSof 74 weeks which was positively correlated with MGMT methylation status and a median PFS of 36 weeks [Butowski et al., 24
ACCEPTED MANUSCRIPT 2011]. Enzastaurin before and concurrently with RT, followed by enzastaurin mainentance therapy in the newly diagnosed MGMT unmethylated GBM, demonstrated median OS of 15 months and PFS-6 of 53.6% (less than primary planned outcome) while it was well tolerated [Wick et al., 2013].
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A phase II trial of enzastaurin and bevacizumab in recurrent GBM is underway (NCT00586508). Tamoxifen, an antiestrogen, has been long described to act also as a PKC inhibitor [Baltuch et al.,
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1993]. Generally, tamoxifen has not been proved to be effective in the treatment of malignant
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gliomas [Spence et al., 2004]. In a phase II trial of RT plus high dose tamoxifen in GBM the median survival time was 9.7 months with a lower than expected thromboembolic incidence, a fact
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attributed to the PKC inhibitory effects of tamoxifen [Robins et al., 2006].
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Cyclopamine, is a specific SHH signaling pathway antagonist of Smoothened (SMO). In vitro studies show that it leads to depletion of stem-like cells in GBM [Bar et al., 2007]. Also, it produces a significant but incomplete GBM xenograft cell regression [Sarangi et al., 2009]. SEN450, a novel
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Smoothened receptor antagonist, seems to be cytostatic on its own and it further reduces tumor
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volume after TMZ pretreatment in vivo and in vitro [Ferruzzi et al., 2012]. Vismodegib (GDC-0449,
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HhAntag691), is a potent novel and specific SHH pathway inhibitor. It has been granted FDA approval for basal cell carcinoma [Meiss et al., 2014]. Vismodegib is being investigated in a phase II study of patients with recurrent GBM that are operatable (NCT00980343). Erismodegib (LDE225), a novel oral SHH pathway inhibitor and a selective Smoothened antagonist, suppresses epithelialmesenchymal transition and self-renewal of GBM cells through modulation of miRNA-200, -128 and -21 [Fu et al., 2013]. Gamma secretase inhibitors (GSIs) are investigated in malignant gliomas to block the Notch mathway [Stockhausen et al., 2012; Lin et al., 2010]. RO4929097 is an oral GSI that sensitizes GBM cells to TMZ in vivo and in vitro [Hiddingh et al., 2014]. It is under evaluation in recurrent/progressive GBM (phase II, NCT01122901). MK-0752 is a moderately potent gamma secretase inhibitor. It has been used in a phase I study of children wth refractory CNS malignancies and was well tolerated [Fouladi et al., 2011]. DAPT (GSI-IX) is a novel GSI that suppresses GBM growth in xenografts via uncoupling of tumor vessel density from vessel function as evidenced by 25
ACCEPTED MANUSCRIPT poor perfusion and aggravated hypoxia [Zou et al., 2013]. Recently, a study showed that alpha secretase inhibitors (ASIs) may be an alternative to GSIs in GBM since it decreased Notch activity and tumor size and increased survival time (compared to GSIs) in GBM cells [Floyd et al., 2012].
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Cilengitide (EMD121974) is a synthetic Arg-Gly-Asp pentapeptide (RGD) that recognizes the RGD ligand binding site on the integrin receptors αVβ3 and αVβ5 and competitively blocks integrin
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ligand binding [Reardon et al., 2008 a]. A phase II study of cilengitide in patients with recurrent
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GBM, demonstrated a PFS-6 of 15% and median OSof 9.9 months. It was generally well tolerated [Reardon et al., 2008 b]. A phase I/IIa study on cilengitide and TMZ/RT followed by the
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administration of cilengitide and TMZ as maintenance was conducted in newly diagnosed GBM,
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according to MGMT status of the patients. Results showed PFS-6 in 69% and PFS at 12 months in 33% of patients, median PFS at 8 months, OSof 68% (at one year) and 35% (at 2 years) and median OSof 16.1 months. PFS and OS were longer in patients with MGMT promoter methylation. The
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combination was well tolerated [Stupp et al., 2010 a]. A similar phase II study to verify the safety of
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cilengitide plus standard chemoradiation (TMZ/RT) also in newly diagnosed GBM was performed.
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The suggested dose was 2000mg and in this group, the median survival was 20.8 months, and regarding MGMT methylation status median survival was 30 months in patients with methylated MGMT and 17.4 months in the unmethylated status subgroup. It was generally well tolerated [Nabors et al., 2012]. In NABTC 03-02 phase II trial evidence of the efficacy of cilengitide was found to be modest as monotherapy in recurrent GBM while it was adequately delivered into the tumor [Gilbert et al., 2012]. Completed trials with cilengitide include, (a) cilengitide, TMZ and RT in newly diagnosed GBM and MGMT promoter methylation (phase III – CENTRIC trial- NCT00689221), (b) cilengitide, TMZ, RT in newly diagnosed GBM and unmethylated MGMT promoter (phase II – CORE trial – NCT00813943), and (c) Cilengitide in patients undergoing surgery for recurrent or progressive GBM (NCT00112866). Results are pending. Thalidomide has been considered as an older antiangiogenic agent [Wen et al., 2008]. It has been associated specifically with a decrease in the expression of adhesion molecules and especially integrins and thus is postulated to inhibit cell migration with antiangiogenic and anti-inflammatory 26
ACCEPTED MANUSCRIPT (decrease in leukocyte migration) activity [McCarty et al., 1997]. It is also widely known for its teratogenic potential. Generally, thalidomide has shown to be ineffective in malignant gliomas alone or in various combinations. In a phase II study of thalidomide plus irinotecan in newly
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diagnosed GBM showed limited efficacy compared to the standard approach while venous thromboembolism was common [Fadul et al., 2008]. In a phase II study on thalidomide combined
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with RT in newly diagnosed GBM did not improve survival [Alexander et al., 2013]. Studies with the
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more potent analogue of thalidomide, lenalidomide are under way including a combination of lenalidomide along with RT in newly diagnosed GBM (NCT00165477). In a phase I trial, lenalidomide
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monotherapy did not seem to be efficient with the added risk of thromboembolic disease [Fine et
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al., 2007]. Increased thromboembolic risk was also found in a phase I study of lenalidomide plus RT in newly-diagnosed GBM [Drappatz et al., 2009].
Multitargeted tyrosine kinase inhibitors (MTKIs): Many tyrosine kinase inhibitors can
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antagonize more than one type of kinase, thus it is somewhat arbitrary to classify them. However,
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most MTKIs do tend to have a more predominant inhibitory action against a specific type of kinase.
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MTKIs with effect on EGFR TKI include two reversible inhibitors (lapanitib and vandetanib) as well as an irreversible inhibitor (Bay846). Lapatinib (GW572016) is a reversible MTKI with dual action on EGFR/ERbB-1 and Her-2/ERbB2 family of receptors. In a phase I/II trial in recurrent GBM, did not show any significant efficacy and when given with anti-epileptic medication, its clearance increased about 1,000%. Neither EGFRvIII excpression, nor PTEN loss could predict a favorable subtype [Thiesen et al., 2010]. It has been used along with temozolomide in a phase I trial without any considerable efficacy [Karavasilis et al., 2013]. Lapatinib has also been investigated in combination with pazopanib and is being investigated along with TMZ and radiation therapy in patients with newly diagnosed GBM (NCT01591577). Vandetanib (ZD6474), is a reversible MTKI with action against EGFR, VEGFR-2, -3 and RET. In tumor models, it achieved higher reduction of GBM tumor volume when combined with TMZ than as monotherapy [Jo et al., 2012]. It has already been through phase I and II trials in patients with recurrent GBM that received fractionated radiosurgery [Fields et al., 2012; Kreisl et al., 2012] and it seems to be effective against gliomas 27
ACCEPTED MANUSCRIPT that express the EGFRvIII mutant, too [Yijn et al., 2010]. Autophagy protects glioblastoma cells from the proapoptotic effects of vandetanib and thus it might contribute significantly to the resistance against it [Shen et al., 2013]. Bay846 is a novel irreversible MTKI against EGFR and Her2 and shows
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efficacy in malignant glioma brain tumor cells. Bay846 was more efficient compared to lapanitib and its sensitivity was associated with wild type PTEN in conjuction with the expression of EGFRvIII
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[Longo et al., 2011].
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MTKIs with effevt on VEGFR include cabozanitinib, cediranib, E7080, pazopanib, sorafenib, sunitinib, vandetanib and vatalanib. Cabozantinib (XL184), is a MTKI that inhibits VEGF2, c-MET,
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AXL, TIE2, Flt-3 and RET. In a phase II trial as monotherapy, in the cohort that received the 175mg
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daily dose it showed a response rate of 21% and in the cohort with the better tolerated 125mg daily dose showed PFS-6 in 25% of patients. XL184 also appeared to have modest activity in patients with prior antiangiogenic treatment. It was noted that only a small number of patients developed distant
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or diffuse disease when the neoplasm progressed, indicating antiangiogenic plus anti-invasive
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effects of XL184 [Wen et al., 2010]. Cabozantinib, is probably a promising agent that suppresses
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angiogenesis, tumor growth and metastasis in neoplasms with dysregulated VEGFR and MET signaling [Yakes et al., 2011]. Moreover, two phase II studies on cabozantinib in recurrent (NCT00704288) and newly diagnosed (NCT00960492) GBM are under way. Cediranib, an oral MTKI, antagonizes all VEGFRs (especially VEGFR2), c-Kit and PDGFR. In a phase II study, used as monotherapy in patients with recurrent GBM, it exhibited encouraging results including PFS -6 in 26% of patients, median OSof 7 months and median PFS of 3.5 months. More than half of patients showed radiographic improvement. However, dose reduction or drug interruption was required in over half of the patients due to grade ¾ toxicities such as hypertension (12.9%), diarrhea and fatigue [Batchelor et al., 2010]. Later, a randomized phase III study, compared cediranib as monotherapy or in combination with lomustine to lomustine monotherapy (with cediranibmatched placebo, as control) was performed. Cediranib was used at lower doses relative to the previous phase II study (30 mg/day p.o. as monotherapy or 20 mg/day p.o. when combined with lomustine) and lomustine was administrated p.o. at 110mg/m2. Both monotherapies and 28
ACCEPTED MANUSCRIPT combinations were given every 6 weeks. The PFS-6 in the ceriranib monotherapy arm was lower than the one observed in the previous phase II study (16%). PFS-6 was 34.5% in the combination arm and 24.5% in the control arm [Ahluwalia et al., 2011]. The efficacy of cediranib in gliomas,
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seems to be limited by effective efflux at the brain-blood barrier via P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) [Wang et al., 2012]. Lenvatinib (E7080), an MTKI active
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against VEGF, PDGF and FGF receptors, suppresses tumor cell migration and invasion [Glen et al.,
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2011]. It is currently being investigated in a phase I/II study of the combination of E7080 plus E7050 (a dual c-MET and VEGFR-2 TKI) in patients with recurrent GBM (NCT01433991). Pazopanib
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(GW786034) is an MTKI against VEGFR-1 through -3, PDGFRα/β and c-Kit. In a phase II study on
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patients with recurrent glioblastoma, it was given at 800mg/daily in 4 week cycles. It was generally ineffective with a response rate of just 6%, PFS-6 of 3%, median PSF of 3 months and median survival of 35 weeks. However, radiographic response was observed. It was well tolerated with a
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toxicity profile similar to that of other anti VEGFR agents [Iwamoto et al., 2010 b]. A phase II study
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on pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma has
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demonstrated limited therapeutic results [Reardon et al., 2013]. Sunitinib, another MTKI, is antagonizing VEGFR-1, -2, -3, c-Kit, PDGFRα/β, Flt-3 and colony stimulating factor 1 receptor 9 (CSF1R). It is approved for gastrointestinal stromal tumors (GISTs) and advanced renal cancer [Gan et al., 2009]. In a phase I study on 25 patients with recurrent high-grade gliomas treated with sunitinib plus irinotecan, limited results were demonstrated with radiographic response was noted in only in one patient and PFS -6 months was 25% [Reardon et al., 2011 b]. In a phase II trial of patients with recurrent high grade glioma, although radiographic response was noted, clinical reponse was achieved in none with OSof 3.8 months [Neyns et al., 2011]. In a prospective phase II study, sunitinib monotherapy in patients with recurrent malignant gliomas (GBM or anaplastic astrocytoma) was disappointing and ineffective since it showed zero response rates, and PSF at 6 months of 16.7% and median OS12.6 months in GBM [Pan et al., 2012]. Vatalanib (PTK787/ZK222584)), is an oral VEGFR, PDGFR and c-Kit inhibitor. In a phase I study on vatalanib plus imatinib plus hydroxyurea in recurrent malignant glioma patients, it was found to be well 29
ACCEPTED MANUSCRIPT tolerated at 1000mg b.i.d. [Reardon et al., 2009 b]. In a 2010 phase I/II study on RT plus concomitant/adjuvant TMZ plus vatalanib/ZK222584 in patients with newly diagnosed GBM, the combination was found to be well tolerated and safe. However, the study was discontinued
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because the industry that was developing vatalanib, chose not to carry on and withdrew it [Brandes et al., 2010].
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MTKIs with effect on PDGFR include bosutinib, cediranib, dasatinib, imatinib, nilotinib,
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pazopanib, sorafenib, sunitinib, tandutinib. Bosutinib (SKI-606), inhibits PDGFR, Src/Srk and BCR/ABL tyrosine kinase used in the treatment of chronic myeloid leukemia [Rassi et al., 2013] and
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is currently being evaluated in a phase II study of patients with recurrent GBM (NCT01331291).
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Dasatinib, is an oral MTKI that affects BCR-ABL, the Src family, c-Kit, EPHA2 and PDGFR-β. It binds to both active and inactive ABL kinase domains. It induces apoptosis, auptophagic cell death of GBM cells, inhibits their invasion, alter cell adhesion and motility-migration of GBM cells in vitro. In vitro
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findings are being followed by ongoing preclinical trials in GBM including, (a) dasatinib plus RT/TMZ
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in newly diagnosed GBM, and (b) dasatinib monotherapy in recurrent GBM [Manmeet et al., 2010].
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Dasatinib plus lomustine in recurrent GBM was marked by significant hematological toxicity and suboptimal efficacy [Fransceschi et al., 2012]. A phase I trial of dasatinib plus erlotinib in patients with recurrent malignant gliomas, showed that it is a safe combination on a daily continuous dosing schedule. However no radiographic response was observed and the PFS-6 was 2%. No grade ¾ toxicities were observed and most commonly, dose limiting toxicities were diarrhea and fatigue [Reardon et al., 2012 a]. Dasatinib, does not appear to have any effect in combination with bevacizumab after bevacizumab failure in recurrent heavily pretreated GBM [Lu-Emerson et al., 2011]. P-gp and Bcrp seem to cause active efflux of dasatinib from the brain hence decreasing efficacy [Agarwal et al., 2012]. Imatinib is an oral MTKI that is effective against BCR-ABL, stem cell factor (SCF)/c-Kit, and PDGFR-α/β. Its toxicity profile includes myelosuppression, aplastic anemia, GI effects (nausea, vomiting, diarrhea, GI hemorrhage), liver toxicity (elevated transaminases/ bilirubin), respiratory effects (cough, dyspnea, upper respiratory tract infections, chest pain, pulmonary fibrosis), skin manifestations (erythema multiforme/ Stevens-Johnson syndrome, 30
ACCEPTED MANUSCRIPT pruritus, angioedema), nervous system effects (headache, migraines, central nervous system hemorrhage, peripheral neuropathy, syncopy), fatigue, pyrexia, blurred vision, conjunctivitis, ascites, fluid retention-edema, arthralgias/myalgias and electrolyte disturbances. It is metabolized
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through CYP 3A4 and subjective to drug interactions when this enzyme is induced [Gan et al., 2009]. In a 2005 phase II study, imanitib plus hydroxyurea in adults with recurrent GBM showed 9%
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radiographic response, PFS-6 in 27% of patients and median PFS 14.4 weeks, in a median follow up
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of 58 weeks. It was generally well tolerated and effective in some patients [Reardon et al., 2005]. However, in a later phase I/II study, imatinib mesylate when used in recurrent malignant gliomas as
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monotherapy was largely ineffective with a PFS-6 of 3% for GBM patients. CYP3A4 inducers
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substantially decreased its effectiveness [Wen et al., 2006 b]. In a phase II study the efficacy of imatinib monotherapy in patients with recurrent malignant gliomas was tested. Imatinib was generally well tolerated in the doses that it was administrated and demonstrated limited antitumor
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effects with a PFS-6 of 16% in GBM [Raymond et al., 2008]. In another phase II study imatinib was
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given as neoadjuvant imatinib before either definitive surgery or re-biopsy in GBM cases. Median
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survival was found to be 6.2 months. Imatinib was found in the histological specimens but it was not associated with reduction in either proliferation or other survival mechanisms (according to biochemical evidence of Ki67, AKT, MAPK or p27 level changes) [Razis et al., 2009]. During the same year, a multicentre phase II study of the combination of imatinib plus hydroxyurea in patients with progressive GBM was not found to be associated with clinically important antitumor activity but was well tolerated. PFS-6 was 10.6%, median OSwas 26 weeks and radiographic response was noted in 3.4% of cases. 7% of patients had either grade 3 fatigue, neutropenia, thrombocytopenia [Reardon et al., 2009 a]. Since the combination of hydroxyurea and imatinib had shown mixed results, in 2010, a randomized multicenter open label phase III study was carried out comparing the combination of hydroxyurea plus imatinib versus hydroxyurea alone in patients with recurrent progressive GBM resistant to TMZ. No clinically important differences were found in comparing the two arms thus implying the ineffectiveness of imatinib in recurrent GBM. The median PFS was similar in both arms (6 weeks), and PFS-6 was 5% for the combination arm and 7% for the 31
ACCEPTED MANUSCRIPT monotherapy arm. In the arm with imatinib, toxicities were well tolerated [Dresemann et al., 2010]. Nilotinib, another PDGFR, BCR-ABL and c-Kit inhibitor, is used in chronic myeloid leukemia [Jabbour et al., 2012] and is currently being investigated in a phase II study of patients with recurrent
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malignant gliomas (NCT01140568). Tandutinib (MLN518), a PDGFR, Flt-3 and c-Kit inhibitor [Lehky et al., 2011], has been evaluated in a phase II trial of the combination tandutinib plus bevacizumab
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in recurrent malignant gliomas. The trial is completed and the results are pending (NCT00667394).
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A second study on tantutinib combination in recurrent or progressive GBM is also completed (NCT00379080).
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MTKIs with action against HGF/SF include cabozantinib, crizotinib and MP470. Crizotinib
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(PF02341066), a dual c-MET, ALK inhibitor, has been tried in patients with both c-MET and ALK positive histology. Recently, there was a report of rapid radiographic and clinical improvement after treatment with crizotinib in MET-amplified recurrent GBM [Chi et al., 2012]. Amuvatinib (MP470), a
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novel oral potent c-Met, c-Kit and PDGFR inhibitor has been shown to radiosensitize GBM cells both
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in vivo and in vitro [Welsh et al., 2009]. Three different safety phase I trials have already been
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completed in healthy volunteers [Choy et al., 2012]. Sorafenib is an oral MTKI with targets such as VEGFR-2, -3, Flt-3, PDGFR-β, c-Kit and it also inhibits B-Raf and C-Raf. These inhibitory effects decrease tumor cells and angiogenesis. This drug is commonly used in hepatocellular carcinoma [Guan et al., 2011]. In vitro results of sorafenib plus nutritional factors such as vitamin K1, has demonstrated enhancement of growth inhibition and apoptosis of malignant glioma cells by blocking the Raf/MEK/ERK pathway [Du et al., 2012]. A phase I trial on concurrent RT and TMZ followed by TMZ and sorafenib in newly diagnosed GBM did not appear to improve efficacy compared to historical standard therapy results [Hainsworth et al., 2010]. In a Phase II study, patients with recurrent GBM were treated with sorafenib plus daily TMZ. However, PFS-6 was only 9.4% (only one patient achieved partial response) and this was attributed to drug interactions with CYP3A inducing antiepileptic drugs that lowered sorafenib exposure in these patients [Reardon et al., 2011 c]. In a phase I/II trial with patients with recurrent GBM, the combination of temsirolimus plus sunitinib was discontinued due to zero PFS-6 [Wen et al., 2009]. A 32
ACCEPTED MANUSCRIPT phase II trial of erlotinib along with sorafenib in patients with recurrent or progressive GBM did not have acceptable results as there were pharmacokinetic interactions between the two drugs [Peereboom et al., 2013]. A phase I/II trial of sorafenib combined with erlotinib, tipifanib or
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temsirolimus in recurrent GBM has been completed (NCT00335764). Other molecular targets and drugs: The importance of epigenetic alterations in cancer is
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well appreciated. Histone deacetylases (HDAC) are involved in chromatin structure that organize
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DNA and regulate transcription of genes and are altered in malignant gliomas. HDAC inhibitors have been used in an attempt to halt growth arrest and to promote cancer cell apoptosis. Histone
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acetylases (HATs) and histone hyperacetylation can also degrade HIF-1a and decrease VEGF and
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thus can lead to antiogenetic effects [Galanis et al., 2009]. Treatment with HDACs reduces proliferation of glioblastoma-derived stem cells and induces their differentiation [Alvarez et al., 2014]. Vorinostat (SAHA) is an oral quinolone-based HDAC inhibitor that in a phase II study as
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monotherapy in recurrent GBM demonstrated modest activity with median OSof 5.7 months and
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PFS-6 was achieved in 9 of the first 57 patients (total of 66). Toxicities included hematologic grade 3
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or worse (mainly thrombocytopenia) as well as grade 3 or worse nonhematologic toxicities (fatigue, dehydration, hypernatremia) [Galanis et al., 2009]. Vorinostat in combination with TMZ in high grade gliomas seems to be well tolerated [Lee et al., 2012]. Many trials with vorinostat are ongoing including a phase I/II trial of vorinostat plus TMZ/RT in newly diagnosed GBM (NCT00731731) and in various combinations such as with isotretinoin plus TMZ or bevacizumab plus TMZ/RT. However, it seems that inhibition of HDAC potentiates the evolution of TMZ resistance by MGMT overexpression in vitro [Kitange et al., 2012]. Panobinostat (LBH589) another HDAC inhibitor has been tested in patients with recurrent high-grade gliomas in combination with bevacizumab in a phase I trial, while a phase II study is ongoing [Drappatz et al., 2012]. Romidepsin (FR901228, Depsipeptide), another quinolone-based HDAC inhibitor has been evaluated in a phase I/II trial of patients with recurrent malignant glioma. It was largely ineffective with a median PFS was 8 weeks, PFS-6 was 3% and median survival duration was 34 weeks [Iwamoto et al., 2011]. Trichostatin A
33
ACCEPTED MANUSCRIPT (TSA) is an HDAC inhibitor that promotes apoptosis on GBM cells and potentiates innate immune response against cancer cells in vitro and in vivo [Höring et al., 2013]. Heat shock proteins (Hsp) and specifically Hsp90 are molecular chaperons that assist in
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stabilizing client proteins such as protein kinases and several transcription factors. Hsp90 seem to be vital in maintaining malignant transformation and in increasing the growth, survival and
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invasiveness of cancer cells. It stabilizes surface expression of EGFRvIII and EGFRvIV mutants and
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probably maintains invasiveness of GBM [Pines et al., 2010]. Tanespimycin (17-AAG) is a potent Hsp90 inhibitor. It exhibits in vitro inhibition of GBM cells and synergistic effects with radiation. It
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can also attenuate glioma stem cell radioresistance but not with TMZ [Sauvageot et al., 2009].
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Acquired resistance is found during prolonged exposure of tanespimycin [Gaspar et al., 2009]. The 26S proteasome is a protein complex that degrades ubiquinated proteins. The role of the ubiquitin-proteasome pathway is to regulate intracellular concentrations of specific proteins
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and maintain cellular homeostasis as it is related to regulation of the cell cycle and transcription,
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cell signaling and apoptosis by degrading regulatory proteins such as p53 and cyclin dependent
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kinases or CDKs [Mani et al., 2005]. Bortezomib (PS-341) is a selective reversible inhibitor of the 26S proteasome. In a phase I of recurrent malignant glioma patients, some clinical efficacy was observed. The overall response rate was 3%, PFS-6 was 21% for patients without exposure to enzyme inducing antiepileptics-EIAED and 9% for those exposed, and median PFS was 1.9 months (exposed) versus 2.6 months (for non-exposed). Median OS was 5.8 months (in EIAED exposed patients) versus 6.1 months (in EIAED non-exposed patients [Phurphanich et al., 2010]. A phase II trial of the combination of vorinostat plus bortezomib in recurrent GBM was disappointing and demonstrated an OS of 3.2 months and median TTP of 1.5 months [Friday et al., 2012]. Bortezomib has shown to overcome MGMT-related resistance of GBM cells to TMZ in vitro by inhibiting MGMT with scheduling of administration being critical (bortezomibe should be given prior to TMZ) [Vlachostergios et al., 2013]. Bortezomib acts synergistically along with HDAC inhibitors to eliminate GBM stem-like cells [Asklund et al., 2012]. Marizomib (NPI-0052) is a new proteasome inhibitor that
34
ACCEPTED MANUSCRIPT has been tested in models for glioma [Potts et al., 2011]. The proteasome inhibitor MG132 produces apoptosis of GBM cells and acts as a chemosensitizer in vitro [Zanatto-Filho et al., 2012]. Tranforming-growth factor beta (TGF-β) and in particular the β2 isoform, is considered a
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key factor in malignant glioma progression (TGF-β2 was originally described as “glioblastomaderived T-cell suppressor factor”) and is associated to be associated with the depressed immune
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status of patients with GBM. High plasma and tissue levels of TGF-β2 are associated with poor
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prognosis and advanced disease [Hau et al., 2011]. It seems to also have an essential role in regulation of glioma-stem cells through Smad-dependent induction of LIF and the subsequent
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activation of JAK-STAT pathway [Penuelas et al., 2009]. Trabedersen (AP 12009) an antisense
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oligonucleotide that specifically inhibits TGF-β2mRNA was tried as monotherapy (administered intratumorally by convection enhanced delivery) versus standard chemotherapy (TMZ or PCV) in a recently randomized phase IIb study, of patients with recurrent or refractory malignant gliomas. At
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10 μM, it achieved a median survival of 39.1 months compared with 21.7 months for chemotherapy
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[Bogdahn et al., 2011]. LY2109761 is a TGF-beta receptor I kinase inhibitor that seems to act as a
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radiosensitizer and prolongs survival in vitro and in vivo [Zhang et al., 2011] and may be used as an adjunct to RT/TMZ in GBM [Zhang, Herion et al., 2011]. SRC and SRC-family kinases (SFKs) mediate downstream signaling pathways from several growth factor receptors and they are frequently activated in glioblastoma [Wick et al., 2011]. It is supported that increased invasiveness associated with antiangiogenic treatment with VEGF inhibitors, is mediated through increased SFK signaling and thus, justifying the combination of dasatinib with bevacizumab [Huveldt et al., 2013], however without much success [See dasatinib]. Glutamate was until recently unrecognized as significant in the pathogenesis of the gliomas. Glutamate is produced as a byproduct of glutathione synthesis and is released by the x(c) (-) cystine glutamate receptors in glioma cells. It is involved by either binding on peritumoral Glu receptors or by paracrine/autocrine effects in: a) in seizure induction, b) excitotoxicity, c) Akt/MAPK activation and cell invasion through AMPA receptors, d) inducing focal adhesion kinases, critical for growth factor regulation and integrin-stimulated cell motility/invasion [de Groot and Sontheimer, 35
ACCEPTED MANUSCRIPT 2011]. Talampanel, a well tolerated oral alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor blocker was tested in a phase II trial in patients with newly diagnosed GBM in addition to standard RT/TMZ. When compared with historical results with standard treatment, the
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median survival was 20.3 versus 14.6 months and 2 month-survival was 41.7% versus 26.5% favoring the addition of talampanel [Grossman et al., 2009]. In a phase II trial of talampanel
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monotherapy against recurrent malignant gliomas was disappointing but well tolerated with most
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common toxicities were fatigue, dizziness, ataxia and respectively results for GBM/anaplastic glioma were PFS-6: 4.6%/0%, median PFS: 5.9 weeks/8.9 weeks and OS: 13 weeks/14 months
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[Iwamoto et al., 2010 a]. Riluzole, a glutamate release inhibitor, in combination with LY341495, a
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groupie mGluR inhibitor, seems to act synergistically to inhibit the growth of GBM in vitro [Yelshkaya et al., 2013].
Topoisomerase I inhibitors camptothecin, irinotecan and novel NKTR-102 as well as
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topoisomerase II inhibitors etoposide and teniposide show in vitro efficacy against glioblastoma cell
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lines [Tamura et al., 2012]. Irinotecan and topotecan have been tested on GBM in various
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combinations including TMZ and bevacizumab with irinotecan and have shown some promising results [Sasine et al., 2010]. NKTR-102 is a topoisomerase I inhibitor polymer conjugate that releases irinotecan following administration and is further metabolized to SN-38, is currently being tested in a phase II study of bevacizumab resistant GBM (NCT01663012). Etoposide in a recent meta-analysis was found to improve OS more than iriotecan in patients with high grade gliomas [Leonard et al., 2013]. JAK2/STAT3 pathway, signal transducers and activators of transcription 3, inhibitors have recently risen as approaches for cancer immunotherapy. STAT3 is constitutively active in some GBM cells, helping tumor cells resist apoptosis and enhance local immunosuppression. The non-receptor tyrosine kinase BMX activates STAT3 signaling to maintain self renewal and tumorigenic potential of glioma stem cells and it can serve also as a therapeutic target [Guryanova et al., 2011]. WP1193 in vitro [Sai et al., 2012] and WP1066 in GBM patients [Hussain et al., 2007], are both effective by reducing glioma cell growth as well as reducing glioma stem cell lines. See also manumycin, a FTI. 36
ACCEPTED MANUSCRIPT Double stranded RNA (dsRNA) is an example of pattern recognition agonists. In a phase II study of the immune modulator polyinosinic-polycytifylic (poly-ICLC) acid in patients with recurrent anaplastic glioma, produced discouraging results: 11% radiographic response, PFS-6 24% and
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median survival of 43 weeks [Butowski et al., 2009]. A phase II study of the poly-ICLC plus standard TMZ/RT in newly diagnosed GBM patients, demonstrated improved results relative to historical
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data of standard regimens [Rosenfeld et al., 2010].
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Other experimental therapeutics: C-150, a novel curry spice curcumin nanoformulative derivative, is a multitargeted agent that reduces the transcription activation of NFkB, inhibits PKC-
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alpha, VEGF, Cyclin D1, BCL-XL and promotes differentiation of glioma-initiating cells by inducing
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autophagy in vitro and shows efficacy in vivo [Ozsvári et al., 2013]. When curcumin is coupled to a glioblastoma-directed antibody, it potentiates its antitumor activity [Langone et al., 2013]. Curcumin increases GBM cell sensitivity to TMZ by generating reactive oxygen species and by
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disrupting the AKT/mTOR pathway [Yin et al., 2014]. Niclosamide is an anthelminthic medication
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that has demonstrated anti-tumor effects in vitro, probably mediated through inhibition of
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WNT/CTNNB1-, Notch-, mTOR-, and NF-kB signaling pathways [Wieland et al., 2013]. Aprepitant is an oral neurokinin-1 receptor (NK-1R) antagonist used in treating nausea and vomiting. Substance P is a natural ligand of NK-1R and thus blockage of this pathway seems to inhibit proliferation, induce apoptosis, antiangiogenic and anti-magration effects in preclinical trials [Muñoz et al., 2012]. Artesunate, an antimalarial drug, induces oxidative DNA damage, DNA double-strand breakage and the ATM/ATR damage response in cancer cells [Berdelle et al., 2011] and potentiates erlotinib’s EGFR mediated cytotoxicity [Efferth et al., 2004]. Auranofin, a medication used to treat rheumatoid arthritis, inhibits cytoprotective thioredoxin reductase and cathepsin B. Thioredoxin reductase is upregulated by TNF-alpha-induced apoptosis (ATIA) protein in glioblastoma and protects from oxidative damage whereas cathepsin B promotes GBM growth and invasion, thus proposing auranofin as a GBM treatment adjunct [Kast et al., 2010]. Disulfiram is an oral aldehyde dehydrogenase (ALD) inhibitor and has strong anti-GBM effects. In vitro effects include Pglycoprotein inactivation, MGMT repair function inhibition, superoxide dismutase inhibition which 37
ACCEPTED MANUSCRIPT secondarily inhibits proteosome, induction of oxidative stress, inhibition of DNA methyltransferase, reduction of DNA replication and reduction of NF-kB pathway [Kast and Halatsch, 2012]. Nelfinavir, a protease inhibitor used in the treatment of HIV infection, exhibits anti-GBM potential by binding
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to and limiting the chaperone function of HSP90 [Kast et al., 2012]. Sertraline, an oral selective serotonine reuptake inhibitor (SSRI), demonstrates downregulation of AKT together with TMZ and
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imatinib in vitro [Tzadock et al., 2014]. Captopril, an angiotensin conversion enzyme inhibitor (ACEI)
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inhibits glioblastoma cell synthesis of MMP-2 and MMP-9 thus strongly inhibiting GBM growth and invasion [Tzadock et al., 2014]. Furthermore, GBM cells express AT-1R (67%) and AT-2R (53%) and
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this high expression is associated with a poor prognosis [Arrietta et al]. Coordinated undermining of
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survival paths (CUSP9) project is investigating aprepitant, artesunate, auranofin, captopril, disulfiram, nelfinavir, sertraline, ketoconazole and copper gluconate as adjuvant to low dose TMZ in patients with recurrent GBM [Kast et al., 2013].
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Monoclonal Antibodies: Monoclonal antibodies (MAbs), are targeting immunoglobulins
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that specifically recognize cell surface proteins/receptors as antigens, especially targeted on the
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surface of tumor cells. They are mainly classified on whether they are unconjugated or conjugated (to protein toxins/cytotoxic agents), or radioimmunoconjugates (to radioisotopes). Mabs may be of murine, human, primate or chimeric (murine variable region plus human constant region) origin [Harris et al., 2004]. Examples of anti EGFR chimeric MAbs are cetuximab and MAb 806, whereas examples of humanized MAb are nimotuzumab and panitumumab. Cetuximab, is an unconjugated chimeric murine-human IgG1 MAb which binds to the extracellular domain of the EGFR, thus inhibiting the binding of EGF to its receptor. It has a stronger affinity to EGFR (plus the EGFRvIII) than EGF and TGF-α. It also downregulates EGFR, inhibits cell growth and metastasis, induces apoptosis, inhibits VEGF production and causes antibody dependent cell-mediated cytotoxicity [Fukai et al., 2008]. In recurrent high grade glioma, cetuximab as monotherapy has demonstrated PFS-6 in 9.2% of patients, median OS(OS) of 5 months and average time to progression (TTP) of 2 months. Although patients where stratified according to EGFR amplification, no correlation to response was found [Neyns et al., 2009]. Again in the 38
ACCEPTED MANUSCRIPT recurrent GBM setting, the combination of bevacizumab, irinotecan and cetuximab showed PFS-6 in 30% of patients, median OS 7.2 months and radiographic response of 34% [Hasselbalch et al., 2010]. Amplification of EGFR and the type of EGFR mutation (EGFRvIII or EGFRvIV) may determine
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the outcome in GBM patients treated with cetuximab. Patients with EGFR amplification and lack of EGFRvIII had better OS (p=0.12) than patients with EGFRvIII expression (p=0.08) [Lv et al., 2012]. No
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trials have been publiced with cetuximab as treatment in newly diagnosed high grade gliomas up to
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this date. MAb 806, seems to enhance the efficacy of ionizing radiation in glioma xenografts expressing the EGFRvIII mutation and can inhibit the growth of U87MG [Johns et al., 2012].
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Nimotuzumab, a humanized MAb with preferential binding to high-EGFR-density tissues (e.g
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tumors, sparing normal tissue) has been tested in pediatric recurrent high grade gliomas [MackDonald et al., 2011]. Radiotherapy plus nimotuzumab or placebo in anaplastic astrocytoma and GBM demonstrated excellent safety profile and significant survival bebefit with mean survival
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of 31.06 months in nimotuzumab treated group versus 21.07 for the control group [Solomón et al.,
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2013]. A Chinese Phase II study of nimotuzumab in combination with TMZ/RT demonstrated good
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safety and tolerability without prolonging survival compared to standard therapy [Wang et al., 2014]. Panitumumab (ABX-EGF), a human monoclonal antibody specific for HER-1, has been used in combination with irinotecan for GBM but results have not been published (NCT01017653) [Berezowska et al., 2011]. AMG 595, an anti-EGFRvIII-DM1 immunoconjugate human monoclonal antibody is currently being evaluated in a phase I study patients with recurrent GBM expressing mutant EGFRvIII (NCT01475006). Anti-VEGFR MAbs include bevacizumab, ramucirumab (IMC-1121B) and IMC-18F1. Bevacizumab, is an unconjugated recombinant humanized murine MAb which binds to and neutralizes VEGF-A, preventing the activation of VEGF receptor tyrosine kinases VEGFR-1 and -2. Given i.v., it has an important toxicity profile. Common manifestations of toxicity include hypertension, headache, gastrointestinal effects (abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation), proteinuria, leucopenia, weakness, stomatitis, epistaxis, dyspnea, upper respiratory tract infection and impaired wound healing. Some more rare but severe side-effects are 39
ACCEPTED MANUSCRIPT central nervous system hemorrhage, venous and arterial thromboembolic events, bowel perforation, left ventricular dysfunction, infusion related reactions and nephrotic syndrome [De Fazio et al., 2012]. In the newly diagnosed setting of GBM, since the concern of serious toxicity is
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great enough, assessment of risk versus benefit is important. When patients with MGMT methylation is treated with RT and TMZ without bevacizumab, about 50% survive 2 years [Stupp et
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al., 2009]. So it is of concern whether the addition of bevacizumab will prolong this OSor shorten it
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due to toxicity. Also, there is concern that addition of bevacizumab promotes a more invasive and aggressive tumor hence shortening survival compared to RT/TMZ alone. In a way to avoid the risk, a
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stratification system has been employed to design GBM trials. The recursive partitioning technique
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(RPA) can be used. Preliminary data demonstrated that there is a trend towards longer survival (when compared to standard RT/TMZ treatment) for patients with low RPA class (e.g. poor performance status and older age) but not for patients with a high RPA class when bevacizumab is
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added. However, a longer PFS-6 was achieved with no association to RPA class [Curran et al., 1993;
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Lai et al., 2009]. In a phase II study which was compared the addition of bevacizumab to standard
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RT/TMZ versus standard treatment alone, showed PFS-6 in 77.5% versus 51.6% of patients respectively and median PFS 17 months versus 7 months respectively [Gruber et al., 2009]. A randomized trial of the addition of bevacizumab or placebo in newly diagnosed GBM, did not improve the OS(median 15.7 vs 16.1 months respectively) though it improved the PFS (10.7 vs 7.3 months) but increased symptom burden and the rate of adverse effects led to an attenuation in quality of life [Gilbert et al., 2014]. In the recurrent setting, bevacizumab has been evaluated either alone or in combination with other agents such as irinotecan, etoposide, carboplatin and TMZ. The phase II BRAIN study, evaluated the role of bevacizumab alone or in combination with irinotecan in patients with recurrent GBM. Monotherapy versus combination showed respectively PFS-6 in 42.6% versus 50.3% of patients, objective response 28.2% versus 37.8% and median OSof 9.2 versus 8.7 months. Both groups of patients had superior radiographic response rates, median PFS and PFS-6 in relation to historical controls [Friedman et al., 2009]. However, this study was a non-comparative study, so 40
ACCEPTED MANUSCRIPT it wasn’t designed to compare the two arms. A second study, tested patients with recurrent GBM treated with bevacizumab and it showed a response rate of 35%, PFS-6 in 29% of patients and a median OSof 31 weeks, decreases in cerebral edema, lower needs for corticosteroids and improved
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neurologic function. Patients that experienced later progression, did not show any improvement when irinotecan was added [Kreisl et al., 2009]. After the BRAIN study, there was still dispute on
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whether monotherapy of bevacizumab was of any real benefit but after the second forementioned
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study, FDA rushed into an accelerated approval in 2009 and since then, bevacizumab is the approved monotherapy for recurrent GBM. Clinical benefit was also demonstrated in Japanese
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patients with PFS-6 in 33.9% of patients, median PFS of 3.3 months and median overall survival of
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10.5 months [Nagane et al., 2012]. However, most patients progress and die from the desease within 6-9 months [Kang et al., 2008]. Patients with progression after bevacizumab failure, have no standard options for salvage treatment. Given the lack of effective salvage regimens, possible
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options include treatment, with bevacizumab again until a second or further recurrence in patients
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with high performance status and small non-rapidly enlarging tumors or combinations, with
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targeted therapies that inhibit possible resistance mechanisms such as other growth factors, or circulating progenitor cells [Krashraw et al., 2010]. Other combinations of bevacizumab have been tested such as plus etoposide or TMZ [Reardon et al., 2011 a], plus erlotinib [Sathornsumetee et al., 2007] and bevacizumab with dosedense TMZ [Gilbert et al., 2010]. However, response rate, PFS-6 and OSwhere similar to the bevacizumab monotherapy rates seen in BRAIN study. Ramucirumab (IMC-1121B) (NCT00895180) and Icrucumab (IMC-18F1) are newer monoclonal antibodies that target the VEGF receptors VEGFR-2 and VEGFR-1 respectively. Trials on GBM are under way but not published up to this date [Hsu et al., 2009]. Aflibercept [Hsu et al., 2009] (also known as VEGF trap), is a recombinantly produced soluble peptide-antibody fusion that scavenges VEGF ligand and placental growth factor. In patients with GBM, two separate phase II studies have been published [de Groot et al., 2011; GomezManzano et al., 2008]. Generally it showed minimal activity and specifically demonstrated PFS-6 in 41
ACCEPTED MANUSCRIPT 7.7% of patients, response rate of 18% and median PFS of 3 months [Gomez-Manzano et al., 2008]. Toxicity led to discontinuation of the treatment in a quarter of patients which included hypertension, lymphopenia, fatigue and central nervous system toxicity (cerebral ischemia).
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MAbs against PDGFR-α, include IMC-3G3 and MEDI-575. MEDI-575 is investigated in ongoing phase I/II studies in recurrent GBM patients (NCT01268566) and results are pending. IMC-
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with ovarian cancer (see NCT00895180) [Shah et al., 2010].
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3G3, has shown inhibition of growth (69%) in U118 GBM cell lines and has been tried in patients
Rilotumumab (AMG102), is a fully human MAb that effectively blocks c-Met
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phosphorylation, thus inhibiting c-Met activated signaling pathways [Giordano et al., 2009]. It has
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been shown to radiosensitize GBM cells in vivo and in vitro [Buchanan et al., 2011]. In a phase II study, patients with recurrent GBM treated with rilotunumab. Two cohorts were designed depending on the rilotunumab dose (10 and 20 mg/kg) and respectively median OSwas 6.5 months
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versus 5.4 months and PFS was 4.1 weeks versus 4.3 weeks. No significant statistical difference was
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attained regarding the pretreatment status with bevacizumab. The results were disappointing and
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the most common adverse effects were fatigue, headache and peripheral edema [Wen et al., 2011]. Two more phase II studies are currently underway evaluating the combination of AMG102 and bevacizumab in patients with recurrent malignant glioma (NCT01113398) as well as AMG102 monotherapy in advanced malignant gliomas (NCT00427440). Onartuzumab (MetMAb or OA-5D5), is a novel human, monovalent (one-armed) 5D5 (OA-5D5) anti-c-Met antibody that was found to be effective in reducing proliferation and microvessel density, as well as in increasing apoptosis in U87 GBM cells (c-Met and HGF/scatter factor positive cell lines) [Martens et al., 2006]. A phase II study of onartuzumab in combination with bevacizumab versus bevacizumab alone or onartuzumab alone in patients with recurrent GBM is in progress (NCT01632228). Stem cells: It has been noted earlier that glioma stem cells have proliferative, invasive capabilities and promote angiogenesis. EGFR inhibitors (that reduce the CD133+ population of stem cells), PI3K/Akt/mTOR pathway inhibitors, GSIs, anti-angiogenetic agents (e.g bevacizumab or cediranib to target the vascular niche of glioma stem cells), Notch pathway inhibitors, Hsp90 42
ACCEPTED MANUSCRIPT inhibitors, Sonic hedgehog pathway inhibitors have all been used to block glioma stem cell population and perhaps enhance radiosensitivity. Cell surface molecules on glioma stem cells may be used as pharmacological targets. L1CAM specifically is a glycoprotein that contains a cytoplasmic
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tail, a transmembrane domain and its extracellular domain that is preferentially found in glioma stem cells compared to non-stem cells of GBM tumors. It can either bind with extracellular matrix
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proteins, EGFR, FGFR, α5β1, avb3, neurophilin-1 or with another L1CAM molecule. L1CAM acts as a
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mediator of molecular signals and regulates survival, growth, adhesion, invasion and migration glioma stem cells. Some of its effects may be due to upregulation of Olig2 that suppresses
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p21WAF/CIP1 [Schmidt et al., 2008]. L1CAM expression is increased with mutations of TP53 or
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expression of TGF-beta [Tsuzuki et al., 1998]. L1CAM also contributes in the chemoresistance of GBM cells and stem cells [Held-Feindt et al., 2012]. Blocking L1CAM, seems to be able to suppress tumor growth and prolong survival of tumor cells in vivo [Bao et al., 2008].
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Since malignant gliomas contain many genetic alterations, various viral vectors have been
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employed to transmit therapeutic genes into their neoplasmatic cells and target those alterations.
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The replication oncolytic adenovirus Delta-24-RGD is capable of engaging the complete cellular system within the glioma cells for its own replication and survival. Even resistant glioma stem cells seem to be vulnerable, suggesting autophagy (upregulation of Atg5 in the tumor cells) followed by lysis of the malignant cell [Jiang et al., 2007]. A phase I/II trial in patients with recurrent GBM (NCT01582516) and a phase I trial for patients with recurrent malignant gliomas (NCT00805376) are ongoing. Immunotherapy: Immunotherapy is a promising approach that has demonstrated an ability to specifically eliminate cancer cells without damaging the surrounding healthy tissue. It includes passive and active immunotherapy strategies. Active immunotherapy creates a long-term immune response against the tumor (propably effective against recurrences) and passive immunotherapy involves the transfer of immediately and short-acting effecting molecules. Tumor-specific antigens are processed by antigen presenting cells (APCs) and recognized by lymphocytes. GBM has the
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ACCEPTED MANUSCRIPT ability to modulate the activity of APCs and this is hypothesized from vaccination studies using tumor lysates that have been unsuccesful [Jackson et al., 2013]. Passive immunotherapy utilizes monoclonal antibodies, adoptive cell transfer and cytokine-
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mediated therapies. Targeted monoclonal antibodies that were discussed in the above sections can be lethal to tumor cells by immune-mediated mechanisms as well as by their specific-targeted
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effects. MAbs bind on cancer cell surfaces in a major histocompatibility complex (MHC) unrestricted
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manner and induce GBM cell death by both immune and non-immune mechanisms. Nivolumab, a fully human MAb against programmed death receptor-1 (PD-1), a negative checkpoint regulator
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with immunosuppressive capabilities has been approved for treatment in unresectable malignant
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melanoma in Japan [Deeks et al., 2014]. Ipilimumab is a MAb that binds to cytotoxic T-lymphocyte (CTL)-associated antigen-4 (CTLA-4/CD152) and enhances T-cell activation thus allowing CTLs to destroy the cancer cells. It has been approved for used in malignant melanoma [Karimkhari et al.,
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2014]. Its efficacy in recurrent GBM is being investigated in a phase IIb trial as monotherapy or in
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combination with ipilimumab versus bevacizumab (NCT02017717).
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Adoptive cell transfer uses effector cells that are activated ex vivo and then tranfered to a patient to attack GBM cells. Effector cells can be lymphocyte-activated killer (LAK) cells, CTLs, natural-killer (NK) cells and γδ-T-cells. Results generally have been mixed with good tolerability but the OS was not significantly improved [Dillman et al., 2009]. Newer CTLs that are more specific to tumor-associated antigens like CD133 which show activity against GBM stem cells [Hua et al., 2011] or virus-specific CTLS (e.g. against CMV proteins pp65 and IE1-72 or nucleic acids) are intensively being investigated against GBM [Nair et al., 2014] (NCT00693095, NCT01109095). Genetically modified T-cells with novel artificial chimeric antigen receptors (CAR), can recognize antigens with HLA-independent mechanisms. CARs are fusion molecules of MAb specific for a tumor-antigen and the ζ-chain of the T-cell-receptor (TCR). CAR-modified T-cells have been manufactured against IL-13 receptor alpha 2 (IL13Ra2) [Krebs et al., 2014] and EGFRvIII [Choi et al., 2014]. A phase I/II trial of autologous CARs against EGFRvIII in glioblastoma is in development (NCT01454596). A phase I trial of postsurgical tumoral cavity injection of IL13Ra2 in GBM has been completed (NCT01082926). 44
ACCEPTED MANUSCRIPT Active Immunotherapy – Vaccine strategies: Although we have a vast arsenal of agents to attack the EGFRs in GBM, a large amount of EGFRs still cannot be blocked due to the receptor’s ubiquitous and high level expression. A peptide vaccine, rindopepimut (CDX-110), is directed
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against the novel exon 1-8 junction produced by the EGFRvIII mutation. Recent phase II studies have shown EGFRvIII specific immune response and significantly prolonged TTP and OS in patients
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with newly diagnosed GBM compared to standard care. It represents a promising field of therapy
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in patients with GBM [Del Vecchio et al., 2012]. A phase III study in patients with newly diagnosed GBM is under way [NCT01480479). ITK-1 is a personalized peptide vaccine given in HLA-A24
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positive recurrent or progressive GBM patients [Terasaki et al., 2011].
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Heat shock protein peptide vaccine (HSPPV) uses peptides complexed with Hsp proteins that are effectively used by APCs [See et al., 2011]. Vitespen a heat shock protein (gp96)-peptide complex purified from autologous tumors has been used in phase I/II trials with minimal side-
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effects and clinical responses in early-stage disease [Wood et al., 2009].
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Other peptide vaccines for malignant gliomas include peptides against melanoma/testis
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antigens, viral antigens, cytokine receptors and differentiation antigens [Mithell et al., 2009]. Gene-modified tumor vaccines work in a different way by inducing GBM cells to be more immunogenic, express new antigens and thus give more targets for the immune system to fight against. Using autologous glioma cells modified to secrete either granulocyte/macrophage colony factor (GM-CSF) [214] or TGFβ2 antisense vectors [Fakhrai et al., 2006] or IL-4 [Okada et al., 2007], response has been seen in small trials of progressive or recurrent GBM patients. Evidence shows that microglia is controlled by glioma cells resulting in their support for growth and thus, instead of destroying them they help by contributing to tumor progression. This maybe mediated through colony-stimulating factors, interleukin-6, TGF-β2 and monocyte chemotactic protein-1(MCP-1) that are being produced by glioma cells [Charles et al., 2011]. In turn, microglial cells support the survival, proliferation and invasion of glioma cells via secretion of factors such as EGF, VEGF and stress-inducible-protein-1 (STI1) [Alves et al., 2011].
45
ACCEPTED MANUSCRIPT Dendritic cell (antigen-presenting) vaccines are made from dendritic cells extracted from the patient, then exposed to the antigens of GBM cells and the same (now “primed”) cells are infused back into the patient. In turn, they activate the CD8+ (cytotoxic) T cells and present GBM
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antigen which is now being recognized by the host immune system. Tumor antigens that are being used are HER2, TRP2, Epha 2, GP100 and KI3ra [Lesniak et al., 2011]. Glioma stem cells contribute
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to resistance to chemoradiotherapy, thus introducing dendritic cells against these stem cells (using
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specific antigens such as CD133 and nestin) would be an important therapeutic target. In a nonrandomized phase II study, anti-EGFRvIII dendritic cell tumor vaccine addition to standard first line
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treatment in GBM patients with good performance status, when compared to a matched control
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group from MD Anderson, it resulted in an increase of median OS from 15 to 26 months and an increase in median PFS from 6.3 months to 14.2 months (hazard ration 2.4; P=o.o13 in favor of the vaccination group). The PFS-6 rate after vaccination was 67% (95% CI, 40-83%) and after diagnosis
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was 94% (95%, 67-99%, n=18). The development of antibodies or delayed type hypersensitivity had
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a significant effect on OS. When the tumor relapsed, EGFRvIII expression was lost in 82% (95% CI,
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48-97%). In subcategory analysis, outcomes were improved in both O-MGMT methylated and unmethylated patients. These results demonstrate that in EGFRvIII-positive GBM, outcomes are improved [Sampson et al., 2010]. Other treatment strategies include microglia as gene or factor therapeutic vectors into the central nervous system and glioma tumors. Examples include microglia carrying the LacZ gene [Sawada et al., 1998], inducible thymidine kinase gene or MRI contrast agents [Ribot et al., 2007] or biodegradable nano-vehicles carrying DNA or RNA silencer fragmants into the glioma tumor (Carbon nanotubes) [Zhao et al., 2011]. Microglial cell gene therapy through viral vectors of either adenovirus [Bhat et al., 2002] or lentivirus (the latter using an enhanced GFP gene) [Balcaitis et al., 2005] have also been tried. Intratumoral administration of oncolytic myxoma virus with rapamycin was another approach [Lun et al., 2012]. Although phase III data are lacking, preclinical and phaseI/II trial results, stongly state that immunotherapy is an area with promising results and offer a new weapon aginst this lethal tumor. 46
ACCEPTED MANUSCRIPT 3. Conclusion Research in GBM treatment is ongoing, vast, and rapidly evolving. However, even all this
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data and progression of molecular science it has not been able to battle effectively this tumor. No matter how many different targets are discovered and molecules to aim them are enginered, the
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end result is that we have made only a little progress forward in improving overall survival.
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However, as is seen in this review, every step in the way, new lessons drive us forward and small details help us bypass the presenting obstacles. New targets, novel antagonists, more effective drug
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penetration through the BBB and new methods of manipulating the immune response are all
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puzzles to be solved in the near future.
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4. References
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Conflict of Interest Statement: The authors declare that there are no conflicts of interest.
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Alves T.R., Lima F.R., Kahn S.A., Lobo D. Dubois L.G., Soletti R., et al. (2011). Glioblastoma cells: a heterogenous and fatal tumor interacting with the parenchyma. Life Sci, 89, 532-539.
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ACCEPTED MANUSCRIPT Table 1. Hereditary risk factors for GBM Gene
Associations
Neurofibromatosis type 1 (NF1)
NF1
Neurofibromas
Neurofibromatosis type 2 (NF2)
NF2
Schwannomas, ependymomas,
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Syndrome
meningiomas TP53
Sarcomas, breast cancer,
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Li-Fraumeni syndrome
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leukemia, adrenal cortex carcinoma, medulloblastomas
DNA mismatch
Colorectal adenomas,
cancer (HNPCC/Lynch syndrome), Turcot
repair (MSH2,
adenocarcinoma
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Hereditary non-polyposis colorectal
syndrome, Brain tumor-polyposis
MLH1, MSH6, PMS1, PMS2)
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syndrome (BTPS)
Multiple endocrine neoplasia type 1
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(MEN1), Werner syndrome
MEN1
Primary hyperparathyroidism, pancreatic endocrine tumors, pituitary adenomas
Nevoid basal cell carcinoma syndrome
PTC
Basal cell carcinomas,
(NBSCC), Gorlin-Gotz syndrome
CH
medulloblastomas, ovarian
Tuberous sclerosis complex (TSC)
fibromas TSC1, TSC2
Renal angiomyolipomas, retinal glial hamartomas, cardiac rhabdomyomas
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ACCEPTED MANUSCRIPT Table 2. Current treatment of newly diagnosed GBM# Maximal surgical resection plusa
i) RT plus concomitant and andjuvant TMZ ii)RT plus concomitant and adjuvant BCNU
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#: See text for dosages, RT: radiotherapy, TMZ: temozolomide, PCV: procarbazine, lomustine
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D
MA
NU
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(CCNU), vincristine, BCNU: carmustine,
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ACCEPTED MANUSCRIPT Table 3. Therapeutic categories Chemotherapy
Alkylating drugs
Temozolomide Nitrosureas (carmustine,
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lomustine) Platinum Compounds
Irinotecan,
etoposide,
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cisplatin Vincristine (part of PCV
SC
Vinca Alkaloids
EGFR
ANG1005, Dichloroacetate, RTA 744
1) TKIs (erlotinib, gefitinib, afatinib, dacomitinib) 2) MTKIs (lapatinib, Vandetanib, Bay846)
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D
Targeted Therapy
MA
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Other chemotherapeutic agents
regimen)
3) MAbs (cetuximab, MAb 806,
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nimotuzumab, panitumumab, AMG 595)
VEGFR
1) MTKIs (vatalanib, vandetanib, sunitinib, lenvatinib, pazopanib, cediranib, cabozatinibe, sorafenib) 2) MAbs (bevacizumab, ramucirumab, IMC-18F1 3) VEGF trap (Aflibercept)
PDGFR
1) MTKIs (Imatinib, dasatinib, nilotinib, tandutinib, bosutinib, sunitinib) 2) sTKI (Crenolanib) 3) MAbs (IMC-3G3, MEDI-575)
HGFR
1) MTKIs (cabozatinib, vandetanib,
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ACCEPTED MANUSCRIPT crizotinib, amuvatinib) 2) sTKI (SGX523) 3) MAbs (Rilotunumab, onartuzumab) 1) Cilengitide
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Integrins
2) Lenalidomide, Thalidomide* RAS/RAF/MEK/MAPK
1) FTIs (Tipifarnib, Lonafarnib, manumycin)
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Intracellular pathways
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2) RAF/MEK/MAPK(sorafenib,TLN-4601) PI3K/AKT/mTOR
1) PI3K (XL-147, Buparlisib)
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2) AKT (MK-2206, perifosine)
PKC
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MA
3) mTOR (temsirolimus, sirolimus,
Tamoxifen, enzastaurin Cyclopamine, SEN450, Vismodegib, Erismodegib
NOTCH
Gamma Secretase Inhibitorss (RO4929097, MK-
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targets
4) PI3K/mTOR (XL-765, PI-103, PKI-587)
SHH/Gli1
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Other molecular
everolimus, ridaforolimus)
HDACs
0752, DAPT Vorinostat, panobinostat, romidepsin, trichostatin A)
Hsp
Tanespimycin
Proteasome
Bortezomib, marizomib, MG132
TGF-beta
Trabedersen, LY2109761
SRC, SFKs
dasatinib
Glutamate
Talampanel, riluzole
Topoisomerase
1) Topoisomerase 1 (captothecin,
inhibitors
irinotecan, NKTR-102) 2) Topoisomerase 2 (etoposide,
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ACCEPTED MANUSCRIPT teniposide) PARP-1
Iniparib, ABT-888
Other agents
C-150, aprepitant, artesunate, auranofin,
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disulfiram, nelfinavir, sertraline, captopril, ketoconazole, copper gluconate Cell surface molecule
L1/CAM antagonism
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Stem cell treatment
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targets
Vaccines
1) Peptide vaccines (Rindopepimut, ITK-1,
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Immunotherapy
Delta-24-RGD oncolytic adenovirus
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Viral vectors
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Dendritic cells
2) Gene-modified tumor vaccines
1) microglia as therapeutic vectors 2) viral vectors as gene therapy for microglia WP1193, WP1066
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JAK2/STAT3 pathway
HSPPV, Vitespen)
inhibitors
83
