Clinical Review & Education
Review
Emerging Therapies for Glioblastoma Alissa A. Thomas, MD; Cameron W. Brennan, MD; Lisa M. DeAngelis, MD; Antonio M. Omuro, MD
IMPORTANCE Glioblastoma is the most common primary malignant brain tumor, but despite
multimodal treatment with surgery, radiotherapy, and temozolomide chemotherapy, the prognosis is poor, with a median survival of 16 to 19 months and poor quality of life throughout the disease course. New treatments are needed. EVIDENCE REVIEW Articles were identified through a search of PubMed references from March 2005 through January 2014, using the terms glioblastoma, glioma, malignant glioma, and brain neoplasm, as well as by search of the authors’ files. Clinical trials were identified in the Clinicaltrials.gov registry. FINDINGS Advances in the understanding of the molecular biology of glioblastoma are being rapidly translated into innovative clinical trials, capitalizing on improved genomic, epigenetic, transcriptional, and proteomic characterization of glioblastomas as well as host factors, including the brain microenvironment and immune system interactions. Therapies targeting tumor growth factor receptors and downstream pathways, angiogenesis, modulation of cancer stemlike cells, cell cycle regulation, oncolytic viruses, new radiotherapy techniques, and immunotherapy, including vaccines and modulation of immune checkpoints (eg, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4), are under investigation. In addition to novel agents, techniques to circumvent the blood-brain barrier to facilitate central nervous system drug exposure are being developed. CONCLUSIONS AND RELEVANCE Glioblastoma is an aggressive tumor with heterogeneous molecular features and complex host interactions, many of which are amenable to therapeutic intervention. Meaningful treatment advances will depend on identifying agents that target mechanistic vulnerabilities that are relevant to specific subgroups of patients; increasing patient enrollment into clinical trials is essential to accelerate the development of patient-tailored treatments. JAMA Neurol. 2014;71(11):1437-1444. doi:10.1001/jamaneurol.2014.1701 Published online September 22, 2014.
G
lioblastoma is the most common primary brain tumor, with an annual incidence of 3.19 per 100 000 in the United States.1,2 The current standard of care combines maximal surgical resection, followed by radiotherapy with concomitant and adjuvant temozolomide.3 Despite this multimodal approach, median survival is limited to 16 to 19 months, with approximately 25% to 30% of the patients alive at 2 years after diagnosis.1,3,4 Patients whose tumors display epigenetic silencing of the DNA repair enzyme O-methyl-guanine-methyltransferase experience better outcomes.4,5 In a recent phase 3 trial4 examining an intensified dosing regimen of temozolomide, patients with methylated O-methyl-guanine-methyltransferase promoter tumors achieved an overall survival length of 21 months vs 14 months for patients with unmethylated tumors and progression-free survival of 9 months vs 6 months. Unfortunately, glioblastoma progresses in all patients, regardless of the tumor’s molecular characteristics. At disease progression, traditional cytotoxic chemotherapy (carmustine, lomustine, or carboplatin) is of little help.1 Bevacizumab, a monojamaneurology.com
Author Affiliations: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York (Thomas, DeAngelis, Omuro); Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York (Brennan). Corresponding Author: Antonio M. Omuro, MD, Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 ([email protected]). Section Editor: David E. Pleasure, MD.
clonal antibody targeting angiogenesis through modulation of the vascular endothelial growth factor pathway, has received conditional approval from the US Food and Drug Administration based on 2 promising phase 2 studies 6,7 that demonstrated high response rates (28.3%7 and 37.8%6) and prolonged progressionfree survival (16 weeks7), although improvements in overall survival remain to be demonstrated. More recently, 2 phase 3 studies 8,9 combining bevacizumab with standard chemotherapy and radiotherapy in patients with newly diagnosed disease have found improved progression-free survival but not overall survival. Given the poor survival with currently approved treatments, new therapeutic options for glioblastoma are clearly needed. Fortunately, rapid advances are being made in understanding glioblastoma tumor genetics. The present review focuses on how these advances are being translated into innovative treatments currently being tested in clinical trials. A review published recently in JAMA1 focused on standard treatment and current trends in the routine clinical management of this disease. JAMA Neurology November 2014 Volume 71, Number 11
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Methods Articles were identified through a search of PubMed references from March 2005 through January 2014, using the terms glioblastoma, glioma, malignant glioma, and brain neoplasm, as well as by search of the authors’ files. Clinical trials were identified in the Clinicaltrials.gov registry.
Advances in Molecular Classification of Glioblastoma Glioblastomas are histologically and genomically heterogeneous tumors and have historically been classified by clinical presentation as either primary or secondary depending on evidence of a preexisting lower-grade glioma. Recent genomic analyses10-13 further support the hypothesis that these 2 clinical scenarios reflect distinct tumor etiologies. The single most common site of mutation in primary glioblastoma, by far the most frequent glioblastoma type, is within the promoter region of the telomerase reverse transcriptase gene (TERT; OMIM 187270), with mutations seen in 54% to 83% of the tumors. TERT promoter mutations are associated with higher levels of messenger RNA expression and may be an important contributing factor behind the strong activation of telomerase function seen in primary glioblastoma.14,15 The same TERT mutations are found in the large majority of oligodendrogliomas as well, but they are much less common in grade II and III astrocytoma and are mutually exclusive with mutations of ATRX (OMIM 300032) and IDH1 (OMIM 147700), which are highly prevalent in those tumors and associated secondary glioblastomas.11,13 Acknowledging the high molecular complexity of these tumors, primary glioblastoma was the first solid tumor type to undergo comprehensive genomic, epigenetic, transcriptional, and proteomic analysis by The Cancer Genome Atlas (TCGA) effort. In that effort, TCGA initially analyzed 206 and then 543 primary glioblastoma samples16,17 to define and validate core pathogenic biological pathways. The most common alterations in gene coding sequence appear to target 3 major cancer pathways, as shown in Figure 1: the retinoblastoma protein tumor suppressor pathway, the p53 tumor suppressor pathway, and the receptor tyrosine kinase (RTK) and mitogen-activated protein kinase (MAPK) signaling pathways.16,18 Analysis using TCGA also revealed common patterns in how these pathways are altered. Based on the patterns of gene expression and DNA methylation, several molecular classifications of glioblastoma have been proposed.17-19 With gene expression analyses, TCGA’s cohort of surgically resected, untreated primary glioblastomas was resolved into 4 transcriptomal groups: classical, proneural, mesenchymal, and neural.17,20 The classical transcriptomal subtype is characterized by the gain of chromosome 7 paired with loss of chromosome 10. Epidermal growth factor receptor (EGFR) is focally amplified and mutated in most cases. The most common EGFR (OMIM 131550) mutation is an inframe deletion of exons 2 to 7, termed EGFRvIII, which is expressed in 25% of primary glioblastomas.21 The EGFR point mutations are also prevalent, found in 25% of the tumors overall, with most targeting the extracellular domain rather than the kinase domain. Mutations in the 1438
tumor suppressor gene TP53 (OMIM 191170) are notably absent in this subtype. The proneural signature is associated with a higher incidence of amplifications of platelet-derived growth factor receptor A (PDGFRA; OMIM 173490), often including neighboring RTKs on chromosome 4q12: KDR (OMIM 173490) and KIT (OMIM 164920), as well as overexpression of other oligodendrocytic development genes, such as NKX-2 (OMIM 604612) and Olig2 (OMIM 606386).17 Mutations of TP53 are also common. Mutations in IDH1 are found in a distinct subset of proneural glioblastomas. Mutations in IDH1 have been associated with increased overall survival in gliomas22 and are a hallmark of World Health Organization grades II and III astrocytomas and oligodendrogliomas.23,24 At the epigenetic level, IDH-mutant tumors harbor a striking pattern of hypermethylation of certain DNA promoter regions (ie, glioma-CpG island methylator phenotype [G-CIMP]).25,26 Conversely, most G-CIMP tumors harbor IDH mutations. The G-CIMP and IDH mutations are favorable prognostic markers for glioblastoma overall and are within the proneural subtype. Proneural glioblastomas that are IDH wild-type or non–G-CIMP are associated with particularly aggressive behavior and a poor prognosis.18 Mesenchymal glioblastomas overexpress mesenchymal markers, showing a high prevalence of deletions and silencing mutations of NF1 (OMIM 162200) on chromosome 17q11, leading to decreased expression of neurofibromin.17 Point mutations in PTEN (OMIM 601728) are common in this subgroup, as is the expression of genes in the tumor necrosis factor super-family. Less is known about the neural tumors, which are characterized by the expression of neuronal markers and, frequently, overexpression of EGFR. It is also possible to subclassify glioblastomas by patterns of DNA methylation rather than by gene expression, and this ability strongly distinguishes the G-CIMP subclass described above. The non–G-CIMP DNA methylation subclasses of primary glioblastomas show clear, but not complete, overlap with the transcriptomal subclasses.18,19 Research is underway to determine how the different proposed glioblastoma classifications may be relevant for the development of specific treatments of glioblastoma and interpretation of clinical trial results.
Targeting Pathways of Tumorigenesis Mutations or amplifications of RTK are present in more than twothirds of all primary glioblastomas (Figure 2).16,18 Multiple growth factors depend on RTKs for signal transduction, including plateletderived growth factor, epidermal growth factor, vascular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor, and insulinlike growth factor.27 The general signal transduction mechanism is similar for each of the growth factors. A growth factor binds to its receptor, leading to receptor dimerization followed by autophosphorylation of the intracellular catalytic tyrosine residues. Downstream signaling may involve the phosphoinositide-3kinase (PI3K) pathway or the Ras G protein-coupled receptor pathway.28 Activated PI3K stimulates Akt and the mammalian target of rapamycin, leading to gene transcription and cell survival. The activity of PI3K is regulated by the tumor suppressor gene PTEN.29 Activation of Ras leads to cell proliferation through activity of Raf-1, mitogen-activated protein kinase kinase, and MAPK.28 In glioblas-
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Figure 1. Summary of Major Cancer Pathways Altered by Mutation and DNA Copy Number Aberration in Untreated Primary Glioblastoma From The Cancer Genome Atlas Deletion or mutation
Amplification or mutation
50%
A
90% Overall
0%
EGFR
PDGFRA
MET
FGFR
57%
10%
1.6%
3.2%
50%
66% Combined
PTEN
PIK(3)K
RAS
NF1
41%
25%
1%
10%
AKT pathway
BRAF
MAPK pathway
2%
B
86% Overall
MDM2 7.6%
CDKN2A
CDKN2B
CDKN2C
61%
5.6%
MDM4
TP53
CDK4
Cyclins
CDK6
7.2%
28%
14%
2%
1.6%
Senescence apoptosis
RB1 7.6%
toma, RTK signaling can be amplified through mutations at several points in the pathway, including the receptor itself; for example, EGFR or PDGFR amplification/mutation (67%), mutations in PI3-kinase subunits PIK3CA or PIK3R1 (25%), or haploinsufficiency and/or mutations in pathway regulatory proteins (eg, PTEN and NF1). One or more alterations in PI3K or MAPK pathways are identifiable in more than 90% of primary glioblastomas.18 The RTK signaling pathways are an attractive target for pharmacotherapy because mutations are common, the pathway is relatively well understood, and agents targeting these pathways have been successfulinothercancers.Small-moleculetyrosinekinaseinhibitorscompete for adenosine triphosphate (ATP) binding to the RTK pocket, thereby blocking receptor activation and transduction of postreceptor signals. 30,31 Unfortunately, clinical trials using firstgeneration tyrosine kinase inhibitors of EGFR and PDGFR, as well as the mammalian target of rapamycin, Akt, and more recently, PI3K inhibitors, have had disappointing results in glioblastoma.31 Several facjamaneurology.com
79% Overall
Cell cycle control
Primary glioblastoma shows a high prevalence of mutations, focal DNA amplifications, and deletions targeting genes within the PI3 kinase/mitogen-activated protein kinase (MAPK) pathway (A) and the p53 and retinoblastoma protein tumor suppressor pathways (B). Adapted with permission from Brennan et al.18
tors may explain such dismal outcomes. Most of these trials did not pre-select patients according to the presence of relevant mutations or overexpression of the target or downstream components, which may be essential for the success of targeted agents. Moreover, some ofthetesteddrugshaverelativelypoorpenetrationthroughthebloodbrain barrier and are not specifically active in the presence of mutations seen in glioblastomas. The existence of redundant pathways or feedback loops may also contribute to intrinsic resistance, and the acquisition of resistance-conferring mutations is another possibility. Current trials are trying to overcome these obstacles by focusing on new inhibitors that are more potent and specific to the glioblastoma mutations32 as well as through the use of higher doses in pulsed schedules that may improve blood-brain barrier penetration, in addition to more strict molecular selection of patients. Treatment targeting multiple pathways simultaneously, including multitargeted tyrosine kinase inhibitors, a combination of agents, and calcium signaling blockade,33 is also being explored (Table 1). JAMA Neurology November 2014 Volume 71, Number 11
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Figure 2. Emerging Treatment Strategies in Glioblastoma A
Targeting tumor growth pathways • Growth factor ligands and receptors • Intracellular downstream targets • Cell cycle modulation
of these therapeutic approaches targeting p53 has progressed beyond small phase 1 trials for glioblastoma.34,35 Inhibitors of MDM2 are now entering clinical trials in humans.36 Other cell cycle modulators are under investigation in glioblastomas, including inhibitors of the G2/M checkpoint protein, Wee1.37-39 Inhibition of Wee1 increases sensitivity to DNA damage (such as that induced by chemotherapy), leading to apoptosis, especially in the setting of p53 dysfunction,16,40-42 which provides the rationale for ongoing trials of an oral Wee1 inhibitor, MK1775.
Stem Cell Theory and Therapy B
Tumor/host microenvironment modulation • Angiogenesis • Cancer stemlike cell pathways • Vaccines • Immune checkpoints
C
Overcoming the blood-brain barrier • Transient opening of the barrier (ultrasound, intra-arterial mannitol) • Convection-enhanced delivery • Nanoparticles • Viral vectors • Stem cells for drug/gene delivery
A, Treatment strategies in glioblastoma may target the tumor's growth pathways. B, Treatment strategies also may alter the microenvironment. The light green and gray cells represent tumor cells; orange, glioma stemlike cells; purple, immune effector cells; dark green, immune regulatory cells; and the red line, a blood vessel. C, Treatment must gain access to the tumor by overcoming the blood-brain barrier. The green mass represents a glioblastoma. BAD indicates Bcl-2–associated death promoter; ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor-bound protein 2; GTP, guanosine triphosphate; MDM2, mouse double minute 2 homolog; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; NF1, neurofibromatosis type 1; NFκB, nuclear factor κ-light-chain-enhancer of activated B cells; PDK1, pyruvate dehydrogenase lipoamide kinase isozyme 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α; PIK3R1, phosphatidylinositol 3-kinase regulatory subunit α; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; Raf-1, RAF proto-oncogene serine/threonine-protein kinase; RTK, receptor tyrosine kinase; and SOS, son of sevenless.
Mutations in TP53 or affecting p53 function are highly prevalent in glioblastomas and are present in up to 85% of tumors.16,18 As a tumor-suppressor gene, TP53 is involved in cell cycle regulation, and it acts as a transcription factor.34 Activation of p53 upregulates multiple genes involved in cell cycle arrest and apoptosis. Inactivation of p53 can occur by amplification of the p53 inhibitors MDM2 or MDM4, deletion of the gene coding p53 stabilizer p14/ ARF, or by mutations in TP53, which are typically monoallelic. Small molecules and peptides capable of inhibiting the DNA binding domain of p53 mutants have been developed to restore tumor suppressor function of the remaining wild-type allele.34 To date, none 1440
Despite a growing understanding of the genetic mutations and growth factors that allow for glioblastoma proliferation, little is known about the steps that initiate tumorigenesis. Traditional thinking43 held that terminally differentiated glial cells acquired a series of mutations leading to dedifferentiation and tumor development. However, newer theories43-45 hypothesize that a specific subgroup of cells with neural stem cell properties may be important in the initiation and maintenance of gliomas. True stem cells have 3 qualities that make them unique: self-renewal, extensive proliferative capacity, and multipotentiality.43 Cancer stemlike cells also have the capacity for limitless self-renewal and the ability to repopulate and maintain a heterogeneous tumor.46 Several markers of glioblastoma stemlike cells have been proposed,43,44 including the hematopoietic stem cell marker CD133, although no single marker appears to correlate completely. Phenotypically, glioblastoma stemlike cells are capable of generating spheres in suspension, termed neurospheres. Cancer stemlike cells may become quiescent and enter the cell cycle only when the tumor mass decreases or cues the stem cells to proliferate.46 When quiescent, the cancer stemlike cells may evade cytotoxic chemotherapy and radiotherapy, which target rapidly dividing cells. Moreover, cancer stemlike cells may display other chemoresistance mechanisms, such as expression of multifunctional efflux transporters from the ATP-binding cassette gene family.47 Embryonic signaling pathways have been implicated48,49 in the maintenance of the stem cell–like state and in the interaction with the brain microenvironment. Thus, targeting embryonic pathways, such as Notch, Hedgehog, and Wnt/β-catenin signaling, has emerged as an attractive therapeutic approach in gliomas. An example is targeting of the Notch pathway, which can be accomplished by γ-secretase inhibitors. Preclinical studies50 have suggested that Notch pathway inhibition was synergistic with radiotherapy, an effect linked to modulation of cancer stemlike cells, as well as angiogenesis. Studies using the γ-secretase inhibitor RO4929097 in combination with radiotherapy or bevacizumab have been completed, and the results are awaited. Because of an unfavorable pharmacokinetic profile, the development of RO4929097 has been halted, but further studies with alternative agents are planned.
Immunotherapy In addition to mutations in cell signaling and growth, part of the aggressive nature of the glioblastoma is related to its ability to escape immune system surveillance (Table 2).51 Two important mediators
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Table 1. Agents Targeting Growth Factor Pathways That Are Frequently Activated in Glioblastomaa Agent
EGFR
AEE788
X
Afatinib
X
Axitinib
PDGFR
Dacomitinib
X X
X
Erlobinib
X
Gefitinib
X
Imatinib
VEGF monoclonal antibody
Cetuximab
EGFR monoclonal antibody
DCVax
Dendritic cell vaccine
Ipilimumab
CTLA-4 monoclonal antibody
Nivolumab
PD-1 monoclonal antibody
X
Rindopepimut/CDX110/CellDex
EGFRvIII peptide vaccine
Abbreviations: CTLA-4, cytotoxic T-lymphocyte antigen 4; DCVax, dendritic cell vaccine; EGFR, epidermal growth factor receptor; EGFRvIII, epidermal growth factor receptor with in-frame deletion of exons 2 to 7; PD-1, programmed cell death 1; VEGF, vascular endothelial growth factor.
X
X X
X
Sorafenib
X
X
Sunitinib
X
X
Tandutinib
X X
X
Everolimus
X
Sirolimus
X
Tacrolimus
X
CC-115
X
XL765 (SAR245409)
X
X
XL147 (SAR245408)
X
PX866
X
BKM120 (buparlisib)
X
Abbreviations: EGFR, epidermal growth factor receptor; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; PI3K, phosphoinositide-3-kinase; VEGF, vascular endothelial growth factor. The X indicates that the pathway is activated; empty cells indicate that the pathway is not activated.
of immune system evasion are the checkpoint proteins cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD1), which regulate adaptive immunity. Binding of PD-1 to its ligand, PD-L1, downregulates T-cell activation and leads to enhanced apoptosis of activated tumor-specific T cells.52,53 Similarly, CTLA-4 inhibits T-cell activation. The monoclonal antibodies ipilimumab and nivolumab inhibit CTLA-4 and PD-1, respectively; based on their remarkable efficacy observed in melanoma,54 this combination is now being tested in recurrent glioblastoma. Vaccines for glioblastoma are being investigated as another way to increase the activation of the patient’s immune system. Just as with vaccines against infections, tumor vaccines are used to prime the immune system against a specific antigen. Two types of vaccines are being explored: peptide based and cell based.55 An example of a peptide-basedvaccineisrindopepimut(alsoknownasCDX-110),51,56 which targets EGFRvIII and is being tested in randomized studies in tumors expressing the EGFRvIII mutation. Cell-based vaccination relies on dendritic cells, the critical antigen presenting cells involved in cellmediated immune responses. Dendritic cells are collected from peripheral blood from the patient, exposed to the tumor antigen in vitro, expanded, and returned to the patient.51 The dendritic cells are typically loaded with autologous whole-tumor lysate, removed from the jamaneurology.com
Mechanism
Bevacizumab
X
X
Nintedanib
a
Treatment
X
X
Dovitinib
Vandetanib
PI3K
X
Dasatanib
Lapatinib
mTOR
X
Cabozantinib Cediranib
VEGF
Table 2. Immunotherapy for Glioblastoma
patient at surgery. Studies have shown a significant immune response to dendritic cell vaccination as demonstrated by lymphocyte interferon γ production, increased tumor-specific precursor frequency of CD4+ and CD8+ T cells, and percentages of proliferating CD4+ and CD8+ cells,57 as well as by an increase in CD4+ tumorspecific T cells after vaccination.58 In a phase 2 study,59 77 patients with newly diagnosed glioblastoma received weekly vaccinations of dendritic cells loaded with autologous tumor lysate. The treatment was well tolerated, with a 6-month progression-free survival of 70%. Interesting phase 1 and 2 results have also been reported with a dendritic cell vaccine (DCVax; Northwest Biotherapeutics), which is now being tested in randomized studies. Many challenges remain in the development of glioblastoma immunotherapies. These challenges include highly frequent lymphopenia60 that may result from the use of radiotherapy and temozolomide, as well as immunosuppression associated with corticosteroids, which are frequently required for symptom management. Moreover, better imaging tools will likely be needed to differentiate tumor progression from therapeutic effects and increased inflammatory reaction that could result from effective immunotherapy.
Applying Advances in Radiotherapy Techniques For the past 3 decades, radiotherapy has been delivered in a standard dose and schedule based on studies of maximum efficacy and brain tissue safety. Since then, remarkable improvements in radiotherapy techniques, including stereotactic technology and intensitymodulated radiotherapy, have allowed for better spatial targeting and sparing of normal brain. A potential application for these developments is the possibility of exploring reirradiation for recurrent glioblastoma. To reduce the risks of symptomatic radionecrosis and brain edema, reirradiation has been combined with bevacizumab, which decreases vascular permeability and edema. In one study,61,62 25 patients with recurrent malignant glioma were treated with hypofractionated stereotactic radiotherapy (30 Gy delivered in 5 fractions) in combination with bevacizumab. Among patients with glioblastoma, the 6-month progression-free survival was 65% and median overall survival was 12 months, with most recurrences observed within the treated field. Reirradiation is now being investigated in the randomized setting, and further dose escalation is being tested in a phase 1 trial. Also under investigation is the use of radiotherapy boosts that JAMA Neurology November 2014 Volume 71, Number 11
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could achieve different biological effects, such as addressing radioresistance associated with tumor hypoxia; these boosts include carbon ion and proton radiotherapy techniques, which are now being addressed in randomized studies (http://www.clinicaltrials.gov).
Developing Alternative Delivery Methods to Overcome the Blood-Brain Barrier A significant challenge in treating glioblastoma is the ability of a drug to cross the blood-brain barrier. Several techniques have been explored to circumvent this problem. The use of intra-arterial mannitol for opening the blood-brain barrier has been used in primary central nervous system lymphoma,63 but this technique is impractical because it depends on repeated angiography procedures for a full course of treatment. Convection-enhanced delivery is another means of infusing agents directly into the brain parenchyma through stereotactic placement of small catheters into the tumor bed during craniotomy.64,65 Positive pressure infusion is applied to generate convection flow in the tissue that supplements passive diffusion. However, in addition to the difficulties of delivering repeated doses, doubt remains as to whether meaningful drug concentrations can be delivered throughout the brain using this technique. Nanoparticles are objects generally less than 100 nm in dimension that can be directly infused into the brain via convectionenhanced delivery or through an intraventricular catheter system to deliver local therapy.65 Nanoparticles may be used as carriers to increase the bioavailability of traditional chemotherapeutic drugs, such as temozolomide, doxorubicin hydrochloride, irinotecan hydrochloride, and vincristine sulfate.64-66 Nanotechnology methods can also deliver drug-free magnetic nanoparticles with an iron oxide core that can generate focal hyperthermia in the presence of magnetic fields, causing local cell death.67 Ultrasound is a safe and effective modality to temporarily open the blood-brain barrier in animals.68,69 Ultrasound does not penetrate the skull well, so to deliver ultrasound pulses to the brain, a small transducer is implanted in the epidural space via craniectomy. In a rabbit model,69 this technique reliably opened the bloodbrain barrier focally as measured by extravasation of Evans blue dye and contrast enhancement after gadolinium injection during magnetic resonance imaging. Studies of implantable ultrasound devices are entering clinical trials in humans. Several small viruses are known to cross the blood-brain barrier and cause encephalitic brain infections. Oncolytic measles virus strains are under investigation in treatment of gliomas,70 and genetically engineered viral vectors have been explored in a variety of different delivery strategies. Oncolytic herpes simplex virus may be engineered to convert a nontoxic antiherpetic prodrug into a cytotoxic byproduct, thereby specifically targeting tumor cells. In a different delivery strategy now entering trials in gliomas, an inducible adenovirus vector engineered to express interleukin 12 (IL-12)71 in the presence of the ligand veledimex will be used with the intent of boosting the immune response. Veledimex is a transcription factor that stabilizes the Rheoswitch Therapeutic System promoter components and allows transcription of the IL-12 target gene. Because target gene expression is dependent on the dose and frequency of veledimex administration, the expression of IL-12 can be modulated (turned on and off) by the optimal veledimex dose and sched1442
ule. If proved successful, this strategy could pave the way for the use of vectors expressing other targeted agents in brain tumors. Alternative vectors under study are mesenchymal stem cells, neuralstemcells,andotherlineage-committedprogenitorcells,whichtake advantage of their strong tropism for cancer cells to deliver genes or cytotoxic molecules and disseminate them within the tumor.43
Advancing Clinical Trial Design Clinical trials in glioblastoma are becoming increasingly sophisticated. Correlative studies embedded in these trials aim to identify predictive biomarkers, including histologic, radiographic, or serumbased markers. Contemporary clinical trials in solid tumors rely heavily on tissue sampling before and after drug exposure to determine the presence of intended targets and then observe target modulation achieved with the new agents. Although this approach is more challenging in glioblastoma, creative trial designs have taken advantage of the frequent need for a second resection. However, such studies are typically limited to assessments that can be performed in paraffin-embedded tissue because frozen material is rarely available from both an initial and a second resection. However, advances in neuroimaging have allowed for indirect evaluation of angiogenesis (perfusion magnetic resonance imaging) and tumor metabolism (magnetic resonance spectroscopy) in glioblastoma, in addition to multiple possibilities for positron-emission tomography using new tracers beyond fluorodeoxyglucose. Magnetic resonance spectroscopy allows for noninvasive detection of IDH1 mutations in gliomas based on the cellular metabolite, 2-hydroxygluterate.72 Mutation-specific trials have been increasingly successful in solid tumors, but in glioblastomas, the frequency of mutations, aside from EGFRvIII, is very low. In a recent clinical trial for recurrent glioblastoma,73 the frequency of potentially “drugable” point mutations was evaluated; 38% of patients displayed a mutation, mostly in EGFR, but overall the frequency of each mutation was low. This finding illustrates that molecularly selected trials will require screening of a very large number of patients for the trials to be completed. Moreover, many clinical trials examining solid tumors are now designed based on rare specific mutations, including tumors representing all types of histologic characteristics. It will be important that such trials do not exclude brain tumors, as is often the case because of fears of additional toxicities that occur in this patient population.
Conclusions For a disease with a long history of little hope, patients and physicians can be enthusiastic about the unprecedentedly high number of investigational treatments. There has been an exponential increase in data about the genetics, molecular biology, and immunology of glioblastoma. As more is understood about proliferation, angiogenesis, and immune evasion, which are the hallmarks of this tumor, more therapeutic targets are unveiled. The success of these emerging therapies may require careful selection of patients based on mutations and protein expression unique to their tumor. With patients’ continued participation in clinical trials, as well as very large screening and accrual efforts, hopefully we will soon identify treatments associated with meaningful clinical benefits.
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ARTICLE INFORMATION Accepted for Publication: May 19, 2014. Published Online: September 22, 2014. doi:10.1001/jamaneurol.2014.1701. Author Contributions: Dr Omuro had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition, analysis, or interpretation of data: Thomas. Drafting of the manuscript: Thomas, Brennan, Omuro. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: DeAngelis, Omuro. Study supervision: Brennan, DeAngelis, Omuro. Conflict of Interest Disclosures: None reported. REFERENCES 1. Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013; 310(17):1842-1850. 2. Ostrom QT, Gittleman H, Farah P, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol. 2013;15(suppl 2):ii1-ii56. 3. Stupp R, Mason WP, van den Bent MJ, et al; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. 4. Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31(32):4085-4091. 5. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. 6. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27(28):4733-4740. 7. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5): 740-745. 8. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370 (8):699-708. 9. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370 (8):709-722. 10. Arita H, Narita Y, Fukushima S, et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol. 2013;126(2):267-276. 11. Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low jamaneurology.com
rates of self-renewal. Proc Natl Acad Sci U S A. 2013; 110(15):6021-6026. 12. Nonoguchi N, Ohta T, Oh JE, Kim YH, Kleihues P, Ohgaki H. TERT promoter mutations in primary and secondary glioblastomas. Acta Neuropathol. 2013;126(6):931-937. 13. Koelsche C, Sahm F, Capper D, et al. Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. Acta Neuropathol. 2013;126(6):907-915. 14. Boldrini L, Pistolesi S, Gisfredi S, et al. Telomerase activity and hTERT mRNA expression in glial tumors. Int J Oncol. 2006;28(6):1555-1560. 15. Langford LA, Piatyszek MA, Xu R, Schold SC Jr, Shay JW. Telomerase activity in human brain tumours. Lancet. 1995;346(8985):1267-1268. 16. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061-1068. 17. Verhaak RG, Hoadley KA, Purdom E, et al; Cancer Genome Atlas Research Network. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98-110. 18. Brennan CW, Verhaak RG, McKenna A, et al; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462-477. 19. Sturm D, Bender S, Jones DT, et al. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer. 2014;14(2):92-107. 20. Lai A, Kharbanda S, Pope WB, et al. Evidence for sequenced molecular evolution of IDH1 mutant glioblastoma from a distinct cell of origin. J Clin Oncol. 2011;29(34):4482-4490. 21. Kastenhuber ER, Huse JT, Berman SH, et al. Quantitative assessment of intragenic receptor tyrosine kinase deletions in primary glioblastomas: their prevalence and molecular correlates. Acta Neuropathol. 2014;127(5):747-759.
brain tumors: part 2: PI3K/Akt/PTEN, mTOR, SHH/PTCH and angiogenesis. Expert Rev Anticancer Ther. 2004;4(1):105-128. 29. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275(5308):1943-1947. 30. Omuro AM. Exploring multi-targeting strategies for the treatment of gliomas. Curr Opin Investig Drugs. 2008;9(12):1287-1295. 31. Omuro AM, Faivre S, Raymond E. Lessons learned in the development of targeted therapy for malignant gliomas. Mol Cancer Ther. 2007;6(7): 1909-1919. 32. Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353(19):2012-2024. 33. Karmali RAMY, Maxuitenko Y, Gorman G. Treatment with paclitaxel orotate and carboxyamidotriazole orotate in SC-implanted OVCAR-5 human ovarian tumor xenografts. J Cancer Ther. 2013;4(4):857-871. 34. England B, Huang T, Karsy M. Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. Tumour Biol. 2013;34(4):2063-2074. 35. Lang FF, Bruner JM, Fuller GN, et al. Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol. 2003;21(13):2508-2518. 36. Yuan Y, Liao YM, Hsueh CT, Mirshahidi HR. Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. J Hematol Oncol. 2011;4:16. doi:10.1186/1756-8722-4-16. 37. Igarashi M, Nagata A, Jinno S, Suto K, Okayama H. Wee1+-like gene in human cells. Nature. 1991;353 (6339):80-83. 38. Parker LL, Piwnica-Worms H. Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. Science. 1992;257(5078):1955-1957.
22. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807-1812.
39. Watanabe N, Broome M, Hunter T. Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. EMBO J. 1995;14(9):1878-1891.
23. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8): 765-773. 24. Labussière M, Idbaih A, Wang XW, et al. All the 1p19q codeleted gliomas are mutated on IDH1 or IDH2. Neurology. 2010;74(23):1886-1890.
40. Mizuarai S, Yamanaka K, Itadani H, et al. Discovery of gene expression-based pharmacodynamic biomarker for a p53 context-specific anti-tumor drug Wee1 inhibitor. Mol Cancer. 2009;8:34. doi:10.1186 /1476-4598-8-34.
25. Noushmehr H, Weisenberger DJ, Diefes K, et al; Cancer Genome Atlas Research Network. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510-522.
41. Hirai H, Iwasawa Y, Okada M, et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 2009;8(11):2992-3000.
26. Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483 (7390):479-483.
42. Wang Y, Decker SJ, Sebolt-Leopold J. Knockdown of Chk1, Wee1 and Myt1 by RNA interference abrogates G2 checkpoint and induces apoptosis. Cancer Biol Ther. 2004;3(3):305-313.
27. Newton HB. Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors: part 1: growth factor and Ras signaling pathways. Expert Rev Anticancer Ther. 2003;3(5):595-614.
43. Dietrich J, Imitola J, Kesari S. Mechanisms of disease: the role of stem cells in the biology and treatment of gliomas. Nat Clin Pract Oncol. 2008;5 (7):393-404.
28. Newton HB. Molecular neuro-oncology and development of targeted therapeutic strategies for
44. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med. 2005;353(8):811-822.
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45. Alcantara Llaguno S, Chen J, Kwon CH, et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell. 2009;15(1): 45-56. 46. Panagiotakos G, Tabar V. Brain tumor stem cells. Curr Neurol Neurosci Rep. 2007;7(3):215-220. 47. Dean M. ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia. 2009;14(1):3-9. 48. Takebe N, Ivy SP. Controversies in cancer stem cells: targeting embryonic signaling pathways. Clin Cancer Res. 2010;16(12):3106-3112. 49. Androutsellis-Theotokis A, Leker RR, Soldner F, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442(7104): 823-826. 50. Hovinga KE, Shimizu F, Wang R, et al. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells. 2010;28(6):1019-1029. 51. Thomas A, Fisher JL, Ernstoff MS, Fadul CE. Vaccine-based immunotherapy for glioblastoma. CNS Oncol. 2013;2(4):331-349. 52. Parsa AT, Waldron JS, Panner A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13(1):84-88. 53. Jacobs JF, Idema AJ, Bol KF, et al. Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors. Neuro Oncol. 2009;11(4):394-402. 54. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275-4280. 55. Thomas AA, Ernstoff MS, Fadul CE. Immunotherapy for the treatment of glioblastoma. Cancer J. 2012;18(1):59-68. 56. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged
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progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28(31):4722-4729. 57. Fadul CE, Fisher JL, Hampton TH, et al. Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J Immunother. 2011; 34(4):382-389.
of polymeric nanoparticles for the treatment of malignant glioma. Nanomedicine. 2014;10(1):149-157. 65. Del Burgo LS, Hernandez RM, Orive G, Pedraz JL. Nanotherapeutic approaches for brain cancer management. Nanomedicine. 2014;10(5):905-919. 66. Xi G, Robinson E, Mania-Farnell B, et al. Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment. Nanomedicine.2014;10(2):381-391.
58. Frank MO, Kaufman J, Tian S, et al. Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer. PLoS One. 2010;5 (9):e12367. doi:10.1371/journal.pone.0012367.
67. Wankhede M, Bouras A, Kaluzova M, Hadjipanayis CG. Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy. Expert Rev Clin Pharmacol. 2012;5(2):173-186.
59. Ardon H, Van Gool SW, Verschuere T, et al. Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial. Cancer Immunol Immunother. 2012;61(11):2033-2044.
68. Jalali S, Huang Y, Dumont DJ, Hynynen K. Focused ultrasound-mediated bbb disruption is associated with an increase in activation of AKT: experimental study in rats. BMC Neurol. 2010;10:114. doi:10.1186/1471-2377-10-114.
60. Grossman SA, Ye X, Lesser G, et al; NABTT CNS Consortium. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res. 2011;17(16):54735480. 61. Gutin PH, Iwamoto FM, Beal K, et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys. 2009;75(1): 156-163. 62. Shapiro LQ, Beal K, Goenka A, et al. Patterns of failure after concurrent bevacizumab and hypofractionated stereotactic radiation therapy for recurrent high-grade glioma. Int J Radiat Oncol Biol Phys. 2013;85(3):636-642. 63. Neuwelt EA, Goldman DL, Dahlborg SA, et al. Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol. 1991;9(9):1580-1590. 64. Bernal GM, Lariviere MJ, Mansour N, et al. Convection-enhanced delivery and in vivo imaging
69. Beccaria K, Canney M, Goldwirt L, et al. Opening of the blood-brain barrier with an unfocused ultrasound device in rabbits. J Neurosurg. 2013;119(4):887-898. 70. Allen C, Paraskevakou G, Liu C, et al. Oncolytic measles virus strains in the treatment of gliomas. Expert Opin Biol Ther. 2008;8(2):213-220. 71. Salem ML, Gillanders WE, Kadima AN, et al. Review: novel nonviral delivery approaches for interleukin-12 protein and gene systems: curbing toxicity and enhancing adjuvant activity. J Interferon Cytokine Res. 2006;26(9):593-608. 72. Pope WB, Prins RM, Albert Thomas M, et al. Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy. J Neurooncol. 2012;107(1):197-205. 73. Omuro A, Chan TA, Abrey LE, et al. Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma. Neuro Oncol. 2013;15(2):242-250.
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Review
Emerging Therapies for Glioblastoma Alissa A. Thomas, MD; Cameron W. Brennan, MD; Lisa M. DeAngelis, MD; Antonio M. Omuro, MD
IMPORTANCE Glioblastoma is the most common primary malignant brain tumor, but despite
multimodal treatment with surgery, radiotherapy, and temozolomide chemotherapy, the prognosis is poor, with a median survival of 16 to 19 months and poor quality of life throughout the disease course. New treatments are needed. EVIDENCE REVIEW Articles were identified through a search of PubMed references from March 2005 through January 2014, using the terms glioblastoma, glioma, malignant glioma, and brain neoplasm, as well as by search of the authors’ files. Clinical trials were identified in the Clinicaltrials.gov registry. FINDINGS Advances in the understanding of the molecular biology of glioblastoma are being rapidly translated into innovative clinical trials, capitalizing on improved genomic, epigenetic, transcriptional, and proteomic characterization of glioblastomas as well as host factors, including the brain microenvironment and immune system interactions. Therapies targeting tumor growth factor receptors and downstream pathways, angiogenesis, modulation of cancer stemlike cells, cell cycle regulation, oncolytic viruses, new radiotherapy techniques, and immunotherapy, including vaccines and modulation of immune checkpoints (eg, programmed cell death 1 and cytotoxic T-lymphocyte antigen 4), are under investigation. In addition to novel agents, techniques to circumvent the blood-brain barrier to facilitate central nervous system drug exposure are being developed. CONCLUSIONS AND RELEVANCE Glioblastoma is an aggressive tumor with heterogeneous molecular features and complex host interactions, many of which are amenable to therapeutic intervention. Meaningful treatment advances will depend on identifying agents that target mechanistic vulnerabilities that are relevant to specific subgroups of patients; increasing patient enrollment into clinical trials is essential to accelerate the development of patient-tailored treatments. JAMA Neurol. 2014;71(11):1437-1444. doi:10.1001/jamaneurol.2014.1701 Published online September 22, 2014.
G
lioblastoma is the most common primary brain tumor, with an annual incidence of 3.19 per 100 000 in the United States.1,2 The current standard of care combines maximal surgical resection, followed by radiotherapy with concomitant and adjuvant temozolomide.3 Despite this multimodal approach, median survival is limited to 16 to 19 months, with approximately 25% to 30% of the patients alive at 2 years after diagnosis.1,3,4 Patients whose tumors display epigenetic silencing of the DNA repair enzyme O-methyl-guanine-methyltransferase experience better outcomes.4,5 In a recent phase 3 trial4 examining an intensified dosing regimen of temozolomide, patients with methylated O-methyl-guanine-methyltransferase promoter tumors achieved an overall survival length of 21 months vs 14 months for patients with unmethylated tumors and progression-free survival of 9 months vs 6 months. Unfortunately, glioblastoma progresses in all patients, regardless of the tumor’s molecular characteristics. At disease progression, traditional cytotoxic chemotherapy (carmustine, lomustine, or carboplatin) is of little help.1 Bevacizumab, a monojamaneurology.com
Author Affiliations: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York (Thomas, DeAngelis, Omuro); Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York (Brennan). Corresponding Author: Antonio M. Omuro, MD, Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 ([email protected]). Section Editor: David E. Pleasure, MD.
clonal antibody targeting angiogenesis through modulation of the vascular endothelial growth factor pathway, has received conditional approval from the US Food and Drug Administration based on 2 promising phase 2 studies 6,7 that demonstrated high response rates (28.3%7 and 37.8%6) and prolonged progressionfree survival (16 weeks7), although improvements in overall survival remain to be demonstrated. More recently, 2 phase 3 studies 8,9 combining bevacizumab with standard chemotherapy and radiotherapy in patients with newly diagnosed disease have found improved progression-free survival but not overall survival. Given the poor survival with currently approved treatments, new therapeutic options for glioblastoma are clearly needed. Fortunately, rapid advances are being made in understanding glioblastoma tumor genetics. The present review focuses on how these advances are being translated into innovative treatments currently being tested in clinical trials. A review published recently in JAMA1 focused on standard treatment and current trends in the routine clinical management of this disease. JAMA Neurology November 2014 Volume 71, Number 11
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Methods Articles were identified through a search of PubMed references from March 2005 through January 2014, using the terms glioblastoma, glioma, malignant glioma, and brain neoplasm, as well as by search of the authors’ files. Clinical trials were identified in the Clinicaltrials.gov registry.
Advances in Molecular Classification of Glioblastoma Glioblastomas are histologically and genomically heterogeneous tumors and have historically been classified by clinical presentation as either primary or secondary depending on evidence of a preexisting lower-grade glioma. Recent genomic analyses10-13 further support the hypothesis that these 2 clinical scenarios reflect distinct tumor etiologies. The single most common site of mutation in primary glioblastoma, by far the most frequent glioblastoma type, is within the promoter region of the telomerase reverse transcriptase gene (TERT; OMIM 187270), with mutations seen in 54% to 83% of the tumors. TERT promoter mutations are associated with higher levels of messenger RNA expression and may be an important contributing factor behind the strong activation of telomerase function seen in primary glioblastoma.14,15 The same TERT mutations are found in the large majority of oligodendrogliomas as well, but they are much less common in grade II and III astrocytoma and are mutually exclusive with mutations of ATRX (OMIM 300032) and IDH1 (OMIM 147700), which are highly prevalent in those tumors and associated secondary glioblastomas.11,13 Acknowledging the high molecular complexity of these tumors, primary glioblastoma was the first solid tumor type to undergo comprehensive genomic, epigenetic, transcriptional, and proteomic analysis by The Cancer Genome Atlas (TCGA) effort. In that effort, TCGA initially analyzed 206 and then 543 primary glioblastoma samples16,17 to define and validate core pathogenic biological pathways. The most common alterations in gene coding sequence appear to target 3 major cancer pathways, as shown in Figure 1: the retinoblastoma protein tumor suppressor pathway, the p53 tumor suppressor pathway, and the receptor tyrosine kinase (RTK) and mitogen-activated protein kinase (MAPK) signaling pathways.16,18 Analysis using TCGA also revealed common patterns in how these pathways are altered. Based on the patterns of gene expression and DNA methylation, several molecular classifications of glioblastoma have been proposed.17-19 With gene expression analyses, TCGA’s cohort of surgically resected, untreated primary glioblastomas was resolved into 4 transcriptomal groups: classical, proneural, mesenchymal, and neural.17,20 The classical transcriptomal subtype is characterized by the gain of chromosome 7 paired with loss of chromosome 10. Epidermal growth factor receptor (EGFR) is focally amplified and mutated in most cases. The most common EGFR (OMIM 131550) mutation is an inframe deletion of exons 2 to 7, termed EGFRvIII, which is expressed in 25% of primary glioblastomas.21 The EGFR point mutations are also prevalent, found in 25% of the tumors overall, with most targeting the extracellular domain rather than the kinase domain. Mutations in the 1438
tumor suppressor gene TP53 (OMIM 191170) are notably absent in this subtype. The proneural signature is associated with a higher incidence of amplifications of platelet-derived growth factor receptor A (PDGFRA; OMIM 173490), often including neighboring RTKs on chromosome 4q12: KDR (OMIM 173490) and KIT (OMIM 164920), as well as overexpression of other oligodendrocytic development genes, such as NKX-2 (OMIM 604612) and Olig2 (OMIM 606386).17 Mutations of TP53 are also common. Mutations in IDH1 are found in a distinct subset of proneural glioblastomas. Mutations in IDH1 have been associated with increased overall survival in gliomas22 and are a hallmark of World Health Organization grades II and III astrocytomas and oligodendrogliomas.23,24 At the epigenetic level, IDH-mutant tumors harbor a striking pattern of hypermethylation of certain DNA promoter regions (ie, glioma-CpG island methylator phenotype [G-CIMP]).25,26 Conversely, most G-CIMP tumors harbor IDH mutations. The G-CIMP and IDH mutations are favorable prognostic markers for glioblastoma overall and are within the proneural subtype. Proneural glioblastomas that are IDH wild-type or non–G-CIMP are associated with particularly aggressive behavior and a poor prognosis.18 Mesenchymal glioblastomas overexpress mesenchymal markers, showing a high prevalence of deletions and silencing mutations of NF1 (OMIM 162200) on chromosome 17q11, leading to decreased expression of neurofibromin.17 Point mutations in PTEN (OMIM 601728) are common in this subgroup, as is the expression of genes in the tumor necrosis factor super-family. Less is known about the neural tumors, which are characterized by the expression of neuronal markers and, frequently, overexpression of EGFR. It is also possible to subclassify glioblastomas by patterns of DNA methylation rather than by gene expression, and this ability strongly distinguishes the G-CIMP subclass described above. The non–G-CIMP DNA methylation subclasses of primary glioblastomas show clear, but not complete, overlap with the transcriptomal subclasses.18,19 Research is underway to determine how the different proposed glioblastoma classifications may be relevant for the development of specific treatments of glioblastoma and interpretation of clinical trial results.
Targeting Pathways of Tumorigenesis Mutations or amplifications of RTK are present in more than twothirds of all primary glioblastomas (Figure 2).16,18 Multiple growth factors depend on RTKs for signal transduction, including plateletderived growth factor, epidermal growth factor, vascular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor, and insulinlike growth factor.27 The general signal transduction mechanism is similar for each of the growth factors. A growth factor binds to its receptor, leading to receptor dimerization followed by autophosphorylation of the intracellular catalytic tyrosine residues. Downstream signaling may involve the phosphoinositide-3kinase (PI3K) pathway or the Ras G protein-coupled receptor pathway.28 Activated PI3K stimulates Akt and the mammalian target of rapamycin, leading to gene transcription and cell survival. The activity of PI3K is regulated by the tumor suppressor gene PTEN.29 Activation of Ras leads to cell proliferation through activity of Raf-1, mitogen-activated protein kinase kinase, and MAPK.28 In glioblas-
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Review Clinical Review & Education
Figure 1. Summary of Major Cancer Pathways Altered by Mutation and DNA Copy Number Aberration in Untreated Primary Glioblastoma From The Cancer Genome Atlas Deletion or mutation
Amplification or mutation
50%
A
90% Overall
0%
EGFR
PDGFRA
MET
FGFR
57%
10%
1.6%
3.2%
50%
66% Combined
PTEN
PIK(3)K
RAS
NF1
41%
25%
1%
10%
AKT pathway
BRAF
MAPK pathway
2%
B
86% Overall
MDM2 7.6%
CDKN2A
CDKN2B
CDKN2C
61%
5.6%
MDM4
TP53
CDK4
Cyclins
CDK6
7.2%
28%
14%
2%
1.6%
Senescence apoptosis
RB1 7.6%
toma, RTK signaling can be amplified through mutations at several points in the pathway, including the receptor itself; for example, EGFR or PDGFR amplification/mutation (67%), mutations in PI3-kinase subunits PIK3CA or PIK3R1 (25%), or haploinsufficiency and/or mutations in pathway regulatory proteins (eg, PTEN and NF1). One or more alterations in PI3K or MAPK pathways are identifiable in more than 90% of primary glioblastomas.18 The RTK signaling pathways are an attractive target for pharmacotherapy because mutations are common, the pathway is relatively well understood, and agents targeting these pathways have been successfulinothercancers.Small-moleculetyrosinekinaseinhibitorscompete for adenosine triphosphate (ATP) binding to the RTK pocket, thereby blocking receptor activation and transduction of postreceptor signals. 30,31 Unfortunately, clinical trials using firstgeneration tyrosine kinase inhibitors of EGFR and PDGFR, as well as the mammalian target of rapamycin, Akt, and more recently, PI3K inhibitors, have had disappointing results in glioblastoma.31 Several facjamaneurology.com
79% Overall
Cell cycle control
Primary glioblastoma shows a high prevalence of mutations, focal DNA amplifications, and deletions targeting genes within the PI3 kinase/mitogen-activated protein kinase (MAPK) pathway (A) and the p53 and retinoblastoma protein tumor suppressor pathways (B). Adapted with permission from Brennan et al.18
tors may explain such dismal outcomes. Most of these trials did not pre-select patients according to the presence of relevant mutations or overexpression of the target or downstream components, which may be essential for the success of targeted agents. Moreover, some ofthetesteddrugshaverelativelypoorpenetrationthroughthebloodbrain barrier and are not specifically active in the presence of mutations seen in glioblastomas. The existence of redundant pathways or feedback loops may also contribute to intrinsic resistance, and the acquisition of resistance-conferring mutations is another possibility. Current trials are trying to overcome these obstacles by focusing on new inhibitors that are more potent and specific to the glioblastoma mutations32 as well as through the use of higher doses in pulsed schedules that may improve blood-brain barrier penetration, in addition to more strict molecular selection of patients. Treatment targeting multiple pathways simultaneously, including multitargeted tyrosine kinase inhibitors, a combination of agents, and calcium signaling blockade,33 is also being explored (Table 1). JAMA Neurology November 2014 Volume 71, Number 11
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Figure 2. Emerging Treatment Strategies in Glioblastoma A
Targeting tumor growth pathways • Growth factor ligands and receptors • Intracellular downstream targets • Cell cycle modulation
of these therapeutic approaches targeting p53 has progressed beyond small phase 1 trials for glioblastoma.34,35 Inhibitors of MDM2 are now entering clinical trials in humans.36 Other cell cycle modulators are under investigation in glioblastomas, including inhibitors of the G2/M checkpoint protein, Wee1.37-39 Inhibition of Wee1 increases sensitivity to DNA damage (such as that induced by chemotherapy), leading to apoptosis, especially in the setting of p53 dysfunction,16,40-42 which provides the rationale for ongoing trials of an oral Wee1 inhibitor, MK1775.
Stem Cell Theory and Therapy B
Tumor/host microenvironment modulation • Angiogenesis • Cancer stemlike cell pathways • Vaccines • Immune checkpoints
C
Overcoming the blood-brain barrier • Transient opening of the barrier (ultrasound, intra-arterial mannitol) • Convection-enhanced delivery • Nanoparticles • Viral vectors • Stem cells for drug/gene delivery
A, Treatment strategies in glioblastoma may target the tumor's growth pathways. B, Treatment strategies also may alter the microenvironment. The light green and gray cells represent tumor cells; orange, glioma stemlike cells; purple, immune effector cells; dark green, immune regulatory cells; and the red line, a blood vessel. C, Treatment must gain access to the tumor by overcoming the blood-brain barrier. The green mass represents a glioblastoma. BAD indicates Bcl-2–associated death promoter; ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor-bound protein 2; GTP, guanosine triphosphate; MDM2, mouse double minute 2 homolog; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; NF1, neurofibromatosis type 1; NFκB, nuclear factor κ-light-chain-enhancer of activated B cells; PDK1, pyruvate dehydrogenase lipoamide kinase isozyme 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α; PIK3R1, phosphatidylinositol 3-kinase regulatory subunit α; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; Raf-1, RAF proto-oncogene serine/threonine-protein kinase; RTK, receptor tyrosine kinase; and SOS, son of sevenless.
Mutations in TP53 or affecting p53 function are highly prevalent in glioblastomas and are present in up to 85% of tumors.16,18 As a tumor-suppressor gene, TP53 is involved in cell cycle regulation, and it acts as a transcription factor.34 Activation of p53 upregulates multiple genes involved in cell cycle arrest and apoptosis. Inactivation of p53 can occur by amplification of the p53 inhibitors MDM2 or MDM4, deletion of the gene coding p53 stabilizer p14/ ARF, or by mutations in TP53, which are typically monoallelic. Small molecules and peptides capable of inhibiting the DNA binding domain of p53 mutants have been developed to restore tumor suppressor function of the remaining wild-type allele.34 To date, none 1440
Despite a growing understanding of the genetic mutations and growth factors that allow for glioblastoma proliferation, little is known about the steps that initiate tumorigenesis. Traditional thinking43 held that terminally differentiated glial cells acquired a series of mutations leading to dedifferentiation and tumor development. However, newer theories43-45 hypothesize that a specific subgroup of cells with neural stem cell properties may be important in the initiation and maintenance of gliomas. True stem cells have 3 qualities that make them unique: self-renewal, extensive proliferative capacity, and multipotentiality.43 Cancer stemlike cells also have the capacity for limitless self-renewal and the ability to repopulate and maintain a heterogeneous tumor.46 Several markers of glioblastoma stemlike cells have been proposed,43,44 including the hematopoietic stem cell marker CD133, although no single marker appears to correlate completely. Phenotypically, glioblastoma stemlike cells are capable of generating spheres in suspension, termed neurospheres. Cancer stemlike cells may become quiescent and enter the cell cycle only when the tumor mass decreases or cues the stem cells to proliferate.46 When quiescent, the cancer stemlike cells may evade cytotoxic chemotherapy and radiotherapy, which target rapidly dividing cells. Moreover, cancer stemlike cells may display other chemoresistance mechanisms, such as expression of multifunctional efflux transporters from the ATP-binding cassette gene family.47 Embryonic signaling pathways have been implicated48,49 in the maintenance of the stem cell–like state and in the interaction with the brain microenvironment. Thus, targeting embryonic pathways, such as Notch, Hedgehog, and Wnt/β-catenin signaling, has emerged as an attractive therapeutic approach in gliomas. An example is targeting of the Notch pathway, which can be accomplished by γ-secretase inhibitors. Preclinical studies50 have suggested that Notch pathway inhibition was synergistic with radiotherapy, an effect linked to modulation of cancer stemlike cells, as well as angiogenesis. Studies using the γ-secretase inhibitor RO4929097 in combination with radiotherapy or bevacizumab have been completed, and the results are awaited. Because of an unfavorable pharmacokinetic profile, the development of RO4929097 has been halted, but further studies with alternative agents are planned.
Immunotherapy In addition to mutations in cell signaling and growth, part of the aggressive nature of the glioblastoma is related to its ability to escape immune system surveillance (Table 2).51 Two important mediators
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Table 1. Agents Targeting Growth Factor Pathways That Are Frequently Activated in Glioblastomaa Agent
EGFR
AEE788
X
Afatinib
X
Axitinib
PDGFR
Dacomitinib
X X
X
Erlobinib
X
Gefitinib
X
Imatinib
VEGF monoclonal antibody
Cetuximab
EGFR monoclonal antibody
DCVax
Dendritic cell vaccine
Ipilimumab
CTLA-4 monoclonal antibody
Nivolumab
PD-1 monoclonal antibody
X
Rindopepimut/CDX110/CellDex
EGFRvIII peptide vaccine
Abbreviations: CTLA-4, cytotoxic T-lymphocyte antigen 4; DCVax, dendritic cell vaccine; EGFR, epidermal growth factor receptor; EGFRvIII, epidermal growth factor receptor with in-frame deletion of exons 2 to 7; PD-1, programmed cell death 1; VEGF, vascular endothelial growth factor.
X
X X
X
Sorafenib
X
X
Sunitinib
X
X
Tandutinib
X X
X
Everolimus
X
Sirolimus
X
Tacrolimus
X
CC-115
X
XL765 (SAR245409)
X
X
XL147 (SAR245408)
X
PX866
X
BKM120 (buparlisib)
X
Abbreviations: EGFR, epidermal growth factor receptor; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; PI3K, phosphoinositide-3-kinase; VEGF, vascular endothelial growth factor. The X indicates that the pathway is activated; empty cells indicate that the pathway is not activated.
of immune system evasion are the checkpoint proteins cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD1), which regulate adaptive immunity. Binding of PD-1 to its ligand, PD-L1, downregulates T-cell activation and leads to enhanced apoptosis of activated tumor-specific T cells.52,53 Similarly, CTLA-4 inhibits T-cell activation. The monoclonal antibodies ipilimumab and nivolumab inhibit CTLA-4 and PD-1, respectively; based on their remarkable efficacy observed in melanoma,54 this combination is now being tested in recurrent glioblastoma. Vaccines for glioblastoma are being investigated as another way to increase the activation of the patient’s immune system. Just as with vaccines against infections, tumor vaccines are used to prime the immune system against a specific antigen. Two types of vaccines are being explored: peptide based and cell based.55 An example of a peptide-basedvaccineisrindopepimut(alsoknownasCDX-110),51,56 which targets EGFRvIII and is being tested in randomized studies in tumors expressing the EGFRvIII mutation. Cell-based vaccination relies on dendritic cells, the critical antigen presenting cells involved in cellmediated immune responses. Dendritic cells are collected from peripheral blood from the patient, exposed to the tumor antigen in vitro, expanded, and returned to the patient.51 The dendritic cells are typically loaded with autologous whole-tumor lysate, removed from the jamaneurology.com
Mechanism
Bevacizumab
X
X
Nintedanib
a
Treatment
X
X
Dovitinib
Vandetanib
PI3K
X
Dasatanib
Lapatinib
mTOR
X
Cabozantinib Cediranib
VEGF
Table 2. Immunotherapy for Glioblastoma
patient at surgery. Studies have shown a significant immune response to dendritic cell vaccination as demonstrated by lymphocyte interferon γ production, increased tumor-specific precursor frequency of CD4+ and CD8+ T cells, and percentages of proliferating CD4+ and CD8+ cells,57 as well as by an increase in CD4+ tumorspecific T cells after vaccination.58 In a phase 2 study,59 77 patients with newly diagnosed glioblastoma received weekly vaccinations of dendritic cells loaded with autologous tumor lysate. The treatment was well tolerated, with a 6-month progression-free survival of 70%. Interesting phase 1 and 2 results have also been reported with a dendritic cell vaccine (DCVax; Northwest Biotherapeutics), which is now being tested in randomized studies. Many challenges remain in the development of glioblastoma immunotherapies. These challenges include highly frequent lymphopenia60 that may result from the use of radiotherapy and temozolomide, as well as immunosuppression associated with corticosteroids, which are frequently required for symptom management. Moreover, better imaging tools will likely be needed to differentiate tumor progression from therapeutic effects and increased inflammatory reaction that could result from effective immunotherapy.
Applying Advances in Radiotherapy Techniques For the past 3 decades, radiotherapy has been delivered in a standard dose and schedule based on studies of maximum efficacy and brain tissue safety. Since then, remarkable improvements in radiotherapy techniques, including stereotactic technology and intensitymodulated radiotherapy, have allowed for better spatial targeting and sparing of normal brain. A potential application for these developments is the possibility of exploring reirradiation for recurrent glioblastoma. To reduce the risks of symptomatic radionecrosis and brain edema, reirradiation has been combined with bevacizumab, which decreases vascular permeability and edema. In one study,61,62 25 patients with recurrent malignant glioma were treated with hypofractionated stereotactic radiotherapy (30 Gy delivered in 5 fractions) in combination with bevacizumab. Among patients with glioblastoma, the 6-month progression-free survival was 65% and median overall survival was 12 months, with most recurrences observed within the treated field. Reirradiation is now being investigated in the randomized setting, and further dose escalation is being tested in a phase 1 trial. Also under investigation is the use of radiotherapy boosts that JAMA Neurology November 2014 Volume 71, Number 11
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could achieve different biological effects, such as addressing radioresistance associated with tumor hypoxia; these boosts include carbon ion and proton radiotherapy techniques, which are now being addressed in randomized studies (http://www.clinicaltrials.gov).
Developing Alternative Delivery Methods to Overcome the Blood-Brain Barrier A significant challenge in treating glioblastoma is the ability of a drug to cross the blood-brain barrier. Several techniques have been explored to circumvent this problem. The use of intra-arterial mannitol for opening the blood-brain barrier has been used in primary central nervous system lymphoma,63 but this technique is impractical because it depends on repeated angiography procedures for a full course of treatment. Convection-enhanced delivery is another means of infusing agents directly into the brain parenchyma through stereotactic placement of small catheters into the tumor bed during craniotomy.64,65 Positive pressure infusion is applied to generate convection flow in the tissue that supplements passive diffusion. However, in addition to the difficulties of delivering repeated doses, doubt remains as to whether meaningful drug concentrations can be delivered throughout the brain using this technique. Nanoparticles are objects generally less than 100 nm in dimension that can be directly infused into the brain via convectionenhanced delivery or through an intraventricular catheter system to deliver local therapy.65 Nanoparticles may be used as carriers to increase the bioavailability of traditional chemotherapeutic drugs, such as temozolomide, doxorubicin hydrochloride, irinotecan hydrochloride, and vincristine sulfate.64-66 Nanotechnology methods can also deliver drug-free magnetic nanoparticles with an iron oxide core that can generate focal hyperthermia in the presence of magnetic fields, causing local cell death.67 Ultrasound is a safe and effective modality to temporarily open the blood-brain barrier in animals.68,69 Ultrasound does not penetrate the skull well, so to deliver ultrasound pulses to the brain, a small transducer is implanted in the epidural space via craniectomy. In a rabbit model,69 this technique reliably opened the bloodbrain barrier focally as measured by extravasation of Evans blue dye and contrast enhancement after gadolinium injection during magnetic resonance imaging. Studies of implantable ultrasound devices are entering clinical trials in humans. Several small viruses are known to cross the blood-brain barrier and cause encephalitic brain infections. Oncolytic measles virus strains are under investigation in treatment of gliomas,70 and genetically engineered viral vectors have been explored in a variety of different delivery strategies. Oncolytic herpes simplex virus may be engineered to convert a nontoxic antiherpetic prodrug into a cytotoxic byproduct, thereby specifically targeting tumor cells. In a different delivery strategy now entering trials in gliomas, an inducible adenovirus vector engineered to express interleukin 12 (IL-12)71 in the presence of the ligand veledimex will be used with the intent of boosting the immune response. Veledimex is a transcription factor that stabilizes the Rheoswitch Therapeutic System promoter components and allows transcription of the IL-12 target gene. Because target gene expression is dependent on the dose and frequency of veledimex administration, the expression of IL-12 can be modulated (turned on and off) by the optimal veledimex dose and sched1442
ule. If proved successful, this strategy could pave the way for the use of vectors expressing other targeted agents in brain tumors. Alternative vectors under study are mesenchymal stem cells, neuralstemcells,andotherlineage-committedprogenitorcells,whichtake advantage of their strong tropism for cancer cells to deliver genes or cytotoxic molecules and disseminate them within the tumor.43
Advancing Clinical Trial Design Clinical trials in glioblastoma are becoming increasingly sophisticated. Correlative studies embedded in these trials aim to identify predictive biomarkers, including histologic, radiographic, or serumbased markers. Contemporary clinical trials in solid tumors rely heavily on tissue sampling before and after drug exposure to determine the presence of intended targets and then observe target modulation achieved with the new agents. Although this approach is more challenging in glioblastoma, creative trial designs have taken advantage of the frequent need for a second resection. However, such studies are typically limited to assessments that can be performed in paraffin-embedded tissue because frozen material is rarely available from both an initial and a second resection. However, advances in neuroimaging have allowed for indirect evaluation of angiogenesis (perfusion magnetic resonance imaging) and tumor metabolism (magnetic resonance spectroscopy) in glioblastoma, in addition to multiple possibilities for positron-emission tomography using new tracers beyond fluorodeoxyglucose. Magnetic resonance spectroscopy allows for noninvasive detection of IDH1 mutations in gliomas based on the cellular metabolite, 2-hydroxygluterate.72 Mutation-specific trials have been increasingly successful in solid tumors, but in glioblastomas, the frequency of mutations, aside from EGFRvIII, is very low. In a recent clinical trial for recurrent glioblastoma,73 the frequency of potentially “drugable” point mutations was evaluated; 38% of patients displayed a mutation, mostly in EGFR, but overall the frequency of each mutation was low. This finding illustrates that molecularly selected trials will require screening of a very large number of patients for the trials to be completed. Moreover, many clinical trials examining solid tumors are now designed based on rare specific mutations, including tumors representing all types of histologic characteristics. It will be important that such trials do not exclude brain tumors, as is often the case because of fears of additional toxicities that occur in this patient population.
Conclusions For a disease with a long history of little hope, patients and physicians can be enthusiastic about the unprecedentedly high number of investigational treatments. There has been an exponential increase in data about the genetics, molecular biology, and immunology of glioblastoma. As more is understood about proliferation, angiogenesis, and immune evasion, which are the hallmarks of this tumor, more therapeutic targets are unveiled. The success of these emerging therapies may require careful selection of patients based on mutations and protein expression unique to their tumor. With patients’ continued participation in clinical trials, as well as very large screening and accrual efforts, hopefully we will soon identify treatments associated with meaningful clinical benefits.
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ARTICLE INFORMATION Accepted for Publication: May 19, 2014. Published Online: September 22, 2014. doi:10.1001/jamaneurol.2014.1701. Author Contributions: Dr Omuro had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition, analysis, or interpretation of data: Thomas. Drafting of the manuscript: Thomas, Brennan, Omuro. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: DeAngelis, Omuro. Study supervision: Brennan, DeAngelis, Omuro. Conflict of Interest Disclosures: None reported. REFERENCES 1. Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013; 310(17):1842-1850. 2. Ostrom QT, Gittleman H, Farah P, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol. 2013;15(suppl 2):ii1-ii56. 3. Stupp R, Mason WP, van den Bent MJ, et al; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. 4. Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31(32):4085-4091. 5. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. 6. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27(28):4733-4740. 7. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5): 740-745. 8. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370 (8):699-708. 9. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370 (8):709-722. 10. Arita H, Narita Y, Fukushima S, et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol. 2013;126(2):267-276. 11. Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low jamaneurology.com
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