Author's Accepted Manuscript
Therapeutic Targets in pilocytic astrocytoma based on genetic analysis Gerald F. Reis MD, PhD, Tarik Tihan MD, PhD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(14)00089-8 http://dx.doi.org/10.1016/j.spen.2014.12.001 YSPEN520
To appear in: Semin Pediatr Neurol
Cite this article as: Gerald F. Reis MD, PhD, Tarik Tihan MD, PhD, Therapeutic Targets in pilocytic astrocytoma based on genetic analysis, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2014.12.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Therapeutic Targets in Pilocytic Astrocytoma Based on Genetic Analysis Gerald F. Reis, MD, PhD and Tarik Tihan, MD, PhD UCSF School of Medicine, Department of Pathology, Neuropathology Division, San Francisco, CA
Correspondence address: Tarik Tihan, MD, PhD, Department of Pathology, Neuropathology Division, Room M551, UCSF Medical Center, 505 Parnassus Avenue, San Francisco, CA, 94143-0102. Telephone: 415-476-5236. Telefax: 415-476-7963. E-mail: [email protected]
1
Abstract Pilocytic astrocytoma is the most common astrocytic neoplasm of childhood. Patients have an extremely favorable prognosis after surgical resection, qualifying tumors for a grade I designation by the Word Health Organization. The molecular data on pilocytic astrocytoma supports a key role for BRAF in the pathogenesis of these tumors, with the KIAA1549-BRAF fusion being the most common alteration identified in sporadic cases, particularly those occurring in the posterior fossa. Constitutive activation of the BRAF oncogene leads to downstream activation of the MEK/MAPK/ERK/p16 pathway, which interestingly is also used by cells to activate oncogene-induced senescence. In fact, the presence of an active oncogeneinduced senescence pathway might explain the periods of dormancy and/or spontaneous regression seen in pilocytic astrocytoma. In addition to reviewing the historical evolution, clinicopathologic, predictive, prognostic, and molecular features of pilocytic astrocytoma, we discuss current therapeutic strategies and the caveats that should be considered for the development of therapies that could be used to more effectively treat challenging cases. Individualized treatment will require identification of the type of MAPK alteration since several alterations in BRAF have been described in addition to the KIAA1549-BRAF fusion. Combination regimens would also appear crucial to achieve tumor eradication and prevent the development of drug resistance. Balancing MAPK pathway inhibition with abrogation of an active oncogene-induced senescence should be carefully considered as well to preserve any existing protective pathways. Importantly, pilocytic astrocytomas are largely indolent tumors and care should be taken to avoid overtreatment since aggressive therapy could cause more harm than good.
2
Pilocytic Astrocytoma: Emergence and Definition of an Entity Pilocytic astrocytoma (PA) was initially described as “spongioblastoma” by Bailey and Cushing in 1926 as a group of tumors that occur in the cerebellar region in children and show a long-term postoperative survival.1 The term PA was not adopted until the first World Health Organization (WHO) consensus in the late 1970s,2 and the early literature referred to these tumors as “spongioblastoma,”, “piloid astrocytoma,” or “astrocytoma of the juvenile type”.3
In the first edition of the WHO fascicle, PA was histologically defined as a neoplasm composed predominantly of fusiform cells with long, wavy fibrillary processes, and frequent stellate astrocytes.2 The nuclear chromatin was delicate and occasionally vesicular, and the cytoplasm extended out as unipolar or bipolar elongated processes forming parallel bundles. Tumors frequently contained two distinct components—piloid areas and loose, microcystic spaces. In the posterior fossa, the microcystic spaces often connected with larger cystic structures and replaced the vermis as well as large hemispheric portions of the cerebellum through mass effect. Rosenthal fibers, eosinophilic granular bodies, and hyalinized vessels were frequently present. Endothelial proliferation occurred in association with the cyst wall and was not considered a sign of malignancy. The infratentorial compartment was most commonly involved though supratentorial examples were also reported, particularly near the midline structures. Tumor growth was characteristically slow and largely non-infiltrative. Invasion of the subarachnoid space was frequently present but was not interpreted as a malignant feature since widespread dissemination did not occur. Affected patients were typically children and young adults who were often cured by surgical resection, particularly for tumors occurring in the posterior fossa. Given these features, PA was classified as a WHO grade I astrocytoma and encompassed the
3
terms “cystic and solid cerebellar astrocytoma”, “pilocytic astrocytoma of the juvenile type”, and “optic nerve glioma”.
Immunohistochemical and epidemiologic studies were included in the second iteration of the WHO.4 Positive staining for glial fibrillary acidic protein (GFAP) suggested PA as a glial/astrocytic neoplasm though the degree of staining varied across cases.4
Many additional studies were performed in the ensuing decade, and the third edition of the WHO included a greatly expanded discussion on PA.5 The median age at presentation has often been reported around 10 years.5 While the fundamental histologic definition and grade I designation remained the same, more reliable information on incidence, age and gender distribution, localization, clinical features and prognosis was provided.5 The third edition of the WHO classification scheme practically outlines what we currently know about the clinical features of PA. The evidence supports the concept of PA as a “chronic disease” and the most common astrocytic neoplasm affecting children.6
The pilocytic category of tumors includes the pilomyxoid astrocytoma (PMA) variant. This entity deserves special consideration since PMA differs from PA in a number of important ways. PMA is composed of piloid cells and may be indistinguishable from classical PA on cytological grounds. However, PMA typically contains a prominent myxoid matrix and monomorphous bipolar cells with angiocentric arrangement in addition to generally lacking a biphasic pattern, Rosenthal fibers, and eosinophilic granular bodies.7 Tumors occur most commonly in the hypothalamic/chiasmatic region with less common sites including the thalamus, posterior fossa,
4
brain stem, temporal lobe, and spinal cord.8 PMA has a higher rate of recurrence and CSF dissemination than PA, so the current WHO scheme considers PMA as a WHO grade II neoplasm.5 However, these neoplasms are still distinctly different than the diffuse astrocytomas that are also considered WHO grade II neoplasms.
The term “optic glioma” has been used loosely to describe not only PA involving the optic nerve but also infiltrating gliomas, various hypothalamic tumors, and hamartomatous lesions. While PA is the most frequent glioma involving the optic nerve, the inclusion of other entities has led to a heterogeneous group of tumors with widely varying pathological features and prognoses. This relates to the fact that glial neoplasms occurring at different locations along the optic pathway can have very different molecular and biological characteristics.9 For example, unlike the hypothalamic tumors, PA of the optic nerve has been reported to spontaneously regress even with subtotal resection or without any surgery.10 Therefore, the term optic glioma should be avoided when referring to PA of the optic nerve proper.11
Clinicopathologic Features, Prognostic, and Predictive Factors The incidence of PA is estimated at 0.37 cases per 100,000 persons per year and shows no gender predilection. While PA can arise anywhere within the central nervous system (CNS), the most common location in children and young adults is the posterior fossa. Symptoms associated with this location may include nausea, vomiting, headache, clumsiness, or gait disturbance. Seizures are uncommon. Focal slowly progressive neurologic deficits are the norm, consistent with the tumor’s indolent behavior. Signs can be non-localizing and vary according to tumor location. Patients with involvement of the optic pathway may develop vision loss and proptosis
5
though this is variable and may not occur in some cases. Hypothalamic tumors can cause obesity, diabetes insipidus, obstructive hydrocephalus, and hemiparesis. Tumors of the brain stem tend to occur in the dorsal aspect, presenting as an exophytic mass that sometimes extends into the cerebellopontine angle. Spinal tumors can cause cord compression.
Adult patients with PA generally present with similar clinical manifestations as pediatric patients although some studies suggest that supratentorial tumors occur at higher frequency in adults.12-14 In adults, the overall mean age at diagnosis is typically between 20 and 25 years, but the range is much broader since some series include patients diagnosed well into their sixties.14
PA has an extremely favorable prognosis, generally following a protracted, indolent course after surgical resection. Some series report 100% 5-year survival, and nearly all patients (96%) live to 10 years following surgery.6, 15 Furthermore, occasional examples of spontaneous regression have been well recognized.16, 17 Therefore, the treatment of choice for PA is gross total surgical resection.
PA can rarely undergo malignant transformation, which can be spontaneous or associated with radiation therapy.18, 19 Malignant transformation is characterized histologically by the presence of numerous mitoses and palisading necrosis. However, even these cases can be cured by surgery with or without adjuvant therapy as reported in a subset of patients.5 Since their prognosis has not been considered akin to glioblastoma, the 2007 WHO classification designated anaplastic (malignant) PA without a corresponding grade. It remains to be seen whether a separate grade for such anaplastic tumors is warranted.
6
Molecular Biology of Pilocytic Astrocytoma and the Importance of the MAPK Pathway A growing body of evidence has demonstrated a key role for the MAPK pathway on the biology of PA. The genetic association between Neurofibromatosis Type I (NF-1) and PA is well known, and patients with this condition typically develop bilateral optic nerve PAs.20 Patients with NF-1 have inactivation of the tumor suppressor gene NF1, which encodes neurofibromin, a negative regulator of RAS. Persistent activation of RAS leads to downstream activation of the mTOR pathway and transcription of genes involved in cellular proliferation.21, 22 While some studies reported spontaneous regression and a more indolent course for NF-1 patients compared to sporadic cases,23 a multi-institutional study of PA showed no difference in progression-free survival or overall survival between NF-1 associated and sporadic PAs.24 Nevertheless, the association between PA and NF-1 suggested a link between PA and the MAPK pathway, directing further studies to a careful examination of this pathway. The 1.9-MB gain at chromosome 7q34, resulting from a fusion between KIAA1549 and BRAF genes, was subsequently described by many authors.25-27 This fusion causes a deletion of the amino-terminal domain of BRAF and constitutive activation of its kinase activity.28-30 KIAA1549-BRAF fusion constitutes the most common molecular alteration in sporadic PA and is particularly common among posterior fossa tumors.11, 25, 27, 28, 31-34 Other molecular alterations in the BRAF gene have also been reported, including alternative fusion products,35, 36 rare BRAFV600E mutations,37 BRAF insertions,38 and KRAS mutations.9 How these genetic alterations correlate with tumor location and behavior is not entirely clear although all of them lead to downstream activation of proteins in the MEK/MAPK pathway. Mutations in BRAF have been reported in a host of other cancers
7
including melanomas, lung and gastric cancers, as well as benign lesions such as melanocytic nevi and colorectal polyps.39, 40
The presence of BRAF oncogene alterations and MEK/MAPK activation in PA raises the possibility that these tumors may also be subjected to oncogene-induced senescence (OIS), a key biological mechanism controlling tumor growth and behavior. Cellular senescence refers to the process whereby proliferating cells adopt a state of permanent cell-cycle arrest.41 Normal cells can undergo cellular senescence through oncogene overexpression, and activation of the MAPK pathway has been strongly associated with initiation of the OIS response.41-45 Therefore, OIS activation provides a molecular explanation for the long periods of dormancy and/or spontaneous regression observed in PA.46 Likewise, loss of NF1 leads to hyperactivation of the oncogene KRAS and downstream activation of the MAPK pathway, which can induce senescence through p16 activation.42 In fact, activation of p16 in PA provides further support for the suggestion that these tumors may be subject to OIS.11, 47 Furthermore, the loss of CDKN2A, the gene encoding p16, in PA is associated with worse clinical outcome, suggesting that an intact OIS response is crucial to the indolent biologic behavior in PA.47
The aforementioned studies suggest that variable activation of the MAPK pathway and OIS may explain the variations in biological behavior seen in PA. It remains to be determined which PAs are subject to OIS and which may abrogate this process and behave more aggressively. Correctly identifying this biological mechanism will be crucial to the design of more effective treatment protocols for PA.
8
Pros and Cons of Targeting the MAPK pathway While surgical resection is the treatment of choice for PA, patients with either inoperable disease or tumors not amenable to gross total resection frequently undergo chemotherapy and/or radiation.48 Currently, chemotherapy is the preferred treatment for children younger than 10 years of age because of the significant adverse impact of radiotherapy on neurocognitive development.49 Clinical trials advocate the use of combination chemotherapy with carboplatin and vincristine because they offer lower toxicity in comparison with other agents and regimens.49-51 Radiotherapy is sometimes recommended for older children and adults with subtotal resection or in cases of tumor progression.
One caveat of using radiotherapy to treat tumors with an activated OIS may be the introduction of additional mutations or genetic silencing within crucial checkpoints such as CDKN2A or TP53. Consequently, alterations in these genes may abrogate OIS and lead to tumor progression.52 In fact, some studies have associated anaplastic transformation of low-grade gliomas to prior radiotherapy.18, 19
Given the known molecular alterations in PA, specific inhibitors to kinases in the MAPK pathway could provide ideal targets in the future treatment of PA. Indeed, recent studies using AZD6244 (selumetinib), an extracellular inhibitor of kinase phosphorylation that targets the Ras/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, has demonstrated some promise.48 However, the MAPK pathway is complex, and the development of resistance to single inhibitor therapy represents a potential limitation to this approach.53-55 Furthermore, resistance to AZD6244 given as single-agent therapy has already been reported,56
9
potentially through alterations in MEK1 or Ras activation via PI3 kinase signaling. Rapamycin may provide a useful adjuvant agent in combination chemotherapy as demonstrated for the treatment of NF-1 children with low-grade glioma.57, 58 Salvage therapy with vinblastine alone could be used in pediatric patients with recurrent disease, so radiotherapy may be further delayed.59
Of note, the MAPK pathway has several important regulators, including sprouty family of proteins, Raf kinase inhibitor protein, and the dual-specific MAPK phosphatase.60-67 Because alterations in these factors could impact responsiveness to MAPK pathway inhibitors, designing effective therapies for PA may benefit from elucidating the role these proteins play on the biology of PA.
Guidelines for Treating Pilocytic Astrocytomas Several issues must be considered for successfully establishing effective therapies to PA. First, selection of the therapeutic approach should follow identification of the type of MAPK alteration. For example, a PA bearing the BRAFV600E mutation may benefit from therapy with vemurafenib, which specifically inhibits this mutated form of BRAF. Second, combination regimens would appear crucial for tumor eradication and to prevent the development of drug resistance. Third, balancing MAPK pathway inhibition with abrogation of OIS should be carefully considered to preserve an intact OIS. Certainly, inoperable tumors may require chemotherapy and/or radiotherapy as the first line of treatment. However, radiotherapy should be delayed as much as possible, especially when treating children and NF-1 patients.49-51 It is
10
critical to avoid overtreatment of PA, since aggressive therapy could cause more harm than good.68
11
REFERENCES 1. Bailey P, Cushing H. A classification of the tumors of the glioma group on a histogenetic basis with a correlated study of prognosis. Philadelphia, London: J.B. Lippincott Co; 1926. 2.
Zulch KJ. Histologic typing of tumours of the central nervous system. Vol 21. First Edition. Geneva, World Health Organization; 1979.
3.
Ringertz N, Nordenstam H. Cerebellar astrocytoma. J Neuropathol Exp Neurol. 10(4):343-367, 1951.
4.
Kleihues P, Burger PC, Scheithauer BW. Histologic typing of tumours of the central nervous system. Second Edition. Berlin, Germany: Springer-Verlag Berlin Heidelberg; 1993.
5.
Scheithauer BW, Hawkins C, Tihan T, VanderBerg SR, Burger PC. Pilocytic astrocytoma. In: Louis, DN, Cavenee, WK, Ohgaki, H, Wiestler, OD, eds. WHO classification of tumours of the central nervous system. 4th Edition. Lyon; 2007:14-21.
6.
Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 64(6):479-489, 2005.
7.
Tihan T, Fisher PG, Kepner JL, et al. Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J Neuropathol Exp Neurol. 58(10):1061-1068, 1999.
8.
Komotar RJ, Mocco J, Carson BS, et al. Pilomyxoid astrocytoma: a review. MedGenMed. 6(4):42, 2004.
9.
Forshew T, Tatevossian RG, Lawson AR, et al. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol. 218(2):172181, 2009.
10.
Parsa CF, Hoyt CS, Lesser RL, et al. Spontaneous regression of optic gliomas: thirteen cases documented by serial neuroimaging. Arch Ophthalmol. 119(4):516-529, 2001.
11.
Reis GF, Bloomer MM, Perry A, et al. Pilocytic astrocytomas of the optic nerve and their relation to pilocytic astrocytomas elsewhere in the central nervous system. Mod Pathol. 26(10):1279-87, 2013.
12.
Clark GB, Henry JM, McKeever PE. Cerebral pilocytic astrocytoma. Cancer. 56(5):1128-1133, 1985.
13.
Garcia DM, Fulling KH. Juvenile pilocytic astrocytoma of the cerebrum in adults. A distinctive neoplasm with favorable prognosis. J Neurosurg. 63(3):382-386, 1985.
12
14.
Forsyth PA, Shaw EG, Scheithauer BW, O'Fallon JR, Layton DD, Jr., Katzmann JA. Supratentorial pilocytic astrocytomas. A clinicopathologic, prognostic, and flow cytometric study of 51 patients. Cancer. 72(4):1335-1342, 1993.
15.
Fernandez C, Figarella-Branger D, Girard N, et al. Pilocytic astrocytomas in children: prognostic factors--a retrospective study of 80 cases. Neurosurgery. 53(3):544-553, 2003.
16.
Gunny RS, Hayward RD, Phipps KP, Harding BN, Saunders DE. Spontaneous regression of residual low-grade cerebellar pilocytic astrocytomas in children. Pediatr Radiol. 35(11):1086-1091, 2005.
17.
Legius E, Marchuk DA, Collins FS, Glover TW. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet. 3(2):122-126, 1993.
18.
Dirks PB, Jay V, Becker LE, et al. Development of anaplastic changes in low-grade astrocytomas of childhood. Neurosurgery. 34(1):68-78, 1994.
19.
Tomlinson FH, Scheithauer BW, Hayostek CJ, et al. The significance of atypia and histologic malignancy in pilocytic astrocytoma of the cerebellum: a clinicopathologic and flow cytometric study. J Child Neurol. 9(3):301-310, 1994.
20.
Lewis RA, Gerson LP, Axelson KA, Riccardi VM, Whitford RP. von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology. 91(8):929-935, 1984.
21.
Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1associated human and mouse brain tumors. Cancer Res. 65(7):2755-2760, 2005.
22.
Chen YH, Gutmann DH. The molecular and cell biology of pediatric low-grade gliomas. Oncogene. 33(16): 2019-26, 2014.
23.
Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg. 85(1):56-65, 1996.
24.
Tihan T, Ersen A, Qaddoumi I, et al. Pathologic characteristics of pediatric intracranial pilocytic astrocytomas and their impact on outcome in 3 countries: a multi-institutional study. Am J Surg Pathol. 36(1):43-55, 2012.
25.
Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol. Sep 67(9):878-887, 2008.
26.
Deshmukh H, Yeh TH, Yu J, et al. High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. Oncogene. 27(34):4745-4751, 2008.
13
27.
Pfister S, Janzarik WG, Remke M, et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 118(5):17391749, 2008.
28.
Jones DT, Kocialkowski S, Liu L, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 68(21):8673-8677, 2008.
29.
Ciampi R, Knauf JA, Kerler R, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest. 115(1):94-101, 2005.
30.
Tran NH, Wu X, Frost JA. B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. J Biol Chem. 280(16):16244-16253, 2005.
31.
Jacob K, Albrecht S, Sollier C, et al. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer. 101(4):722-733, 2009.
32.
Sievert AJ, Jackson EM, Gai X, et al. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol. 19(3):449-458, 2009.
33.
Yu J, Deshmukh H, Gutmann RJ, et al. Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology. 73(19):1526-1531, 2009.
34.
Rodriguez FJ, Ligon AH, Horkayne-Szakaly I, et al. BRAF Duplications and MAPK Pathway Activation Are Frequent in Gliomas of the Optic Nerve Proper. J Neuropathol Exp Neurol. 71(9):789-794, 2012.
35.
Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene. 28(20):2119-2123, 2009.
36.
Cin H, Meyer C, Herr R, et al. Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol. 121(6):763-774, 2011.
37.
Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 121(3):397-405, 2011.
38.
Eisenhardt AE, Olbrich H, Roring M, et al. Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma. Int J Cancer. 129(9):2297-2303, 2011.
14
39.
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 24(22):2463-2479, 2010.
40.
Minoo P, Jass JR. Senescence and serration: a new twist to an old tale. J Pathol. 210(2):137-140, 2006.
41.
Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 8(9):729-740, 2007.
42.
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 88(5):593-602, 1997.
43.
Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12(19):3008-3019, 1998.
44.
Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell death-apoptosis, autophagy and senescence. FEBS J. 277(1):2-21, 2010.
45.
Evan GI, d'Adda di Fagagna F. Cellular senescence: hot or what? Curr Opin Genet Dev. 19(1):25-31, 2009.
46.
Borit A, Richardson EP, Jr. The biological and clinical behaviour of pilocytic astrocytomas of the optic pathways. Brain. 105(Pt 1):161-187, 1982.
47.
Raabe EH, Lim KS, Kim JM, et al. BRAF activation induces transformation and then senescence in human neural stem cells: a pilocytic astrocytoma model. Clin Cancer Res. 17(11):3590-3599, 2011.
48.
Sadighi Z, Slopis J. Pilocytic astrocytoma: a disease with evolving molecular heterogeneity. J Child Neurol. 28(5):625-632, 2013.
49.
Perilongo G. Considerations on the role of chemotherapy and modern radiotherapy in the treatment of childhood low grade glioma. J Neurooncol. 75(3):301-307, 2005.
50.
Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol. 30(21):2641-2647, 2012.
51.
Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg. 86(5):747-754, 1997.
52.
Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol. 14(6):777-789, 2012.
15
53.
Wee S, Jagani Z, Xiang KX, et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 69(10):4286-4293, 2009.
54.
Kolb EA, Gorlick R, Houghton PJ, et al. Initial testing (stage 1) of AZD6244 (ARRY142886) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 55(4):668677, 2010.
55.
Emery CM, Vijayendran KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 106(48):20411-20416, 2009.
56.
Lafay-Cousin L, Holm S, Qaddoumi I, et al. Weekly vinblastine in pediatric low-grade glioma patients with carboplatin allergic reaction. Cancer. 103(12):2636-2642, 2005.
57.
Greger JG, Eastman SD, Zhang V, et al. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther. 11(4):909-920, 2012.
58.
Yalon M, Rood B, MacDonald TJ, et al. A feasibility and efficacy study of rapamycin and erlotinib for recurrent pediatric low-grade glioma (LGG). Pediatr Blood Cancer. 60(1):71-76, 2013.
59.
Bouffet E, Jakacki R, Goldman S, et al. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol. 30(12):1358-1363, 2012.
60.
Courtois-Cox S, Genther Williams SM, Reczek EE, et al. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 10(6):459-472, 2006.
61.
Murphy T, Hori S, Sewell J, Gnanapragasam VJ. Expression and functional role of negative signalling regulators in tumour development and progression. Int J Cancer. 127(11):2491-2499, 2010.
62.
Matheny SA, Chen C, Kortum RL, Razidlo GL, Lewis RE, White MA. Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature. 427(6971):256-260, 2004.
63.
Yeung K, Janosch P, McFerran B, et al. Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol Cell Biol. 20(9):3079-3085, 2000.
64.
Owens DM, Keyse SM. Differential regulation of MAP kinase signalling by dualspecificity protein phosphatases. Oncogene. 26(22):3203-3213, 2007.
65.
Kim HJ, Bar-Sagi D. Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol. 5(6):441-450, 2004.
66.
Boutros T, Chevet E, Metrakos P. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev. 60(3):261-310, 2008. 16
67.
Kwak HJ, Kim YJ, Chun KR, et al. Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene. 30(21):2433-2442, 2011.
68.
Burger PC, Scheithauer BW, Lee RR, O'Neill BP. An interdisciplinary approach to avoid the overtreatment of patients with central nervous system lesions. Cancer. 80(11):20402046, 1997.
17
Therapeutic Targets in pilocytic astrocytoma based on genetic analysis Gerald F. Reis MD, PhD, Tarik Tihan MD, PhD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(14)00089-8 http://dx.doi.org/10.1016/j.spen.2014.12.001 YSPEN520
To appear in: Semin Pediatr Neurol
Cite this article as: Gerald F. Reis MD, PhD, Tarik Tihan MD, PhD, Therapeutic Targets in pilocytic astrocytoma based on genetic analysis, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2014.12.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Therapeutic Targets in Pilocytic Astrocytoma Based on Genetic Analysis Gerald F. Reis, MD, PhD and Tarik Tihan, MD, PhD UCSF School of Medicine, Department of Pathology, Neuropathology Division, San Francisco, CA
Correspondence address: Tarik Tihan, MD, PhD, Department of Pathology, Neuropathology Division, Room M551, UCSF Medical Center, 505 Parnassus Avenue, San Francisco, CA, 94143-0102. Telephone: 415-476-5236. Telefax: 415-476-7963. E-mail: [email protected]
1
Abstract Pilocytic astrocytoma is the most common astrocytic neoplasm of childhood. Patients have an extremely favorable prognosis after surgical resection, qualifying tumors for a grade I designation by the Word Health Organization. The molecular data on pilocytic astrocytoma supports a key role for BRAF in the pathogenesis of these tumors, with the KIAA1549-BRAF fusion being the most common alteration identified in sporadic cases, particularly those occurring in the posterior fossa. Constitutive activation of the BRAF oncogene leads to downstream activation of the MEK/MAPK/ERK/p16 pathway, which interestingly is also used by cells to activate oncogene-induced senescence. In fact, the presence of an active oncogeneinduced senescence pathway might explain the periods of dormancy and/or spontaneous regression seen in pilocytic astrocytoma. In addition to reviewing the historical evolution, clinicopathologic, predictive, prognostic, and molecular features of pilocytic astrocytoma, we discuss current therapeutic strategies and the caveats that should be considered for the development of therapies that could be used to more effectively treat challenging cases. Individualized treatment will require identification of the type of MAPK alteration since several alterations in BRAF have been described in addition to the KIAA1549-BRAF fusion. Combination regimens would also appear crucial to achieve tumor eradication and prevent the development of drug resistance. Balancing MAPK pathway inhibition with abrogation of an active oncogene-induced senescence should be carefully considered as well to preserve any existing protective pathways. Importantly, pilocytic astrocytomas are largely indolent tumors and care should be taken to avoid overtreatment since aggressive therapy could cause more harm than good.
2
Pilocytic Astrocytoma: Emergence and Definition of an Entity Pilocytic astrocytoma (PA) was initially described as “spongioblastoma” by Bailey and Cushing in 1926 as a group of tumors that occur in the cerebellar region in children and show a long-term postoperative survival.1 The term PA was not adopted until the first World Health Organization (WHO) consensus in the late 1970s,2 and the early literature referred to these tumors as “spongioblastoma,”, “piloid astrocytoma,” or “astrocytoma of the juvenile type”.3
In the first edition of the WHO fascicle, PA was histologically defined as a neoplasm composed predominantly of fusiform cells with long, wavy fibrillary processes, and frequent stellate astrocytes.2 The nuclear chromatin was delicate and occasionally vesicular, and the cytoplasm extended out as unipolar or bipolar elongated processes forming parallel bundles. Tumors frequently contained two distinct components—piloid areas and loose, microcystic spaces. In the posterior fossa, the microcystic spaces often connected with larger cystic structures and replaced the vermis as well as large hemispheric portions of the cerebellum through mass effect. Rosenthal fibers, eosinophilic granular bodies, and hyalinized vessels were frequently present. Endothelial proliferation occurred in association with the cyst wall and was not considered a sign of malignancy. The infratentorial compartment was most commonly involved though supratentorial examples were also reported, particularly near the midline structures. Tumor growth was characteristically slow and largely non-infiltrative. Invasion of the subarachnoid space was frequently present but was not interpreted as a malignant feature since widespread dissemination did not occur. Affected patients were typically children and young adults who were often cured by surgical resection, particularly for tumors occurring in the posterior fossa. Given these features, PA was classified as a WHO grade I astrocytoma and encompassed the
3
terms “cystic and solid cerebellar astrocytoma”, “pilocytic astrocytoma of the juvenile type”, and “optic nerve glioma”.
Immunohistochemical and epidemiologic studies were included in the second iteration of the WHO.4 Positive staining for glial fibrillary acidic protein (GFAP) suggested PA as a glial/astrocytic neoplasm though the degree of staining varied across cases.4
Many additional studies were performed in the ensuing decade, and the third edition of the WHO included a greatly expanded discussion on PA.5 The median age at presentation has often been reported around 10 years.5 While the fundamental histologic definition and grade I designation remained the same, more reliable information on incidence, age and gender distribution, localization, clinical features and prognosis was provided.5 The third edition of the WHO classification scheme practically outlines what we currently know about the clinical features of PA. The evidence supports the concept of PA as a “chronic disease” and the most common astrocytic neoplasm affecting children.6
The pilocytic category of tumors includes the pilomyxoid astrocytoma (PMA) variant. This entity deserves special consideration since PMA differs from PA in a number of important ways. PMA is composed of piloid cells and may be indistinguishable from classical PA on cytological grounds. However, PMA typically contains a prominent myxoid matrix and monomorphous bipolar cells with angiocentric arrangement in addition to generally lacking a biphasic pattern, Rosenthal fibers, and eosinophilic granular bodies.7 Tumors occur most commonly in the hypothalamic/chiasmatic region with less common sites including the thalamus, posterior fossa,
4
brain stem, temporal lobe, and spinal cord.8 PMA has a higher rate of recurrence and CSF dissemination than PA, so the current WHO scheme considers PMA as a WHO grade II neoplasm.5 However, these neoplasms are still distinctly different than the diffuse astrocytomas that are also considered WHO grade II neoplasms.
The term “optic glioma” has been used loosely to describe not only PA involving the optic nerve but also infiltrating gliomas, various hypothalamic tumors, and hamartomatous lesions. While PA is the most frequent glioma involving the optic nerve, the inclusion of other entities has led to a heterogeneous group of tumors with widely varying pathological features and prognoses. This relates to the fact that glial neoplasms occurring at different locations along the optic pathway can have very different molecular and biological characteristics.9 For example, unlike the hypothalamic tumors, PA of the optic nerve has been reported to spontaneously regress even with subtotal resection or without any surgery.10 Therefore, the term optic glioma should be avoided when referring to PA of the optic nerve proper.11
Clinicopathologic Features, Prognostic, and Predictive Factors The incidence of PA is estimated at 0.37 cases per 100,000 persons per year and shows no gender predilection. While PA can arise anywhere within the central nervous system (CNS), the most common location in children and young adults is the posterior fossa. Symptoms associated with this location may include nausea, vomiting, headache, clumsiness, or gait disturbance. Seizures are uncommon. Focal slowly progressive neurologic deficits are the norm, consistent with the tumor’s indolent behavior. Signs can be non-localizing and vary according to tumor location. Patients with involvement of the optic pathway may develop vision loss and proptosis
5
though this is variable and may not occur in some cases. Hypothalamic tumors can cause obesity, diabetes insipidus, obstructive hydrocephalus, and hemiparesis. Tumors of the brain stem tend to occur in the dorsal aspect, presenting as an exophytic mass that sometimes extends into the cerebellopontine angle. Spinal tumors can cause cord compression.
Adult patients with PA generally present with similar clinical manifestations as pediatric patients although some studies suggest that supratentorial tumors occur at higher frequency in adults.12-14 In adults, the overall mean age at diagnosis is typically between 20 and 25 years, but the range is much broader since some series include patients diagnosed well into their sixties.14
PA has an extremely favorable prognosis, generally following a protracted, indolent course after surgical resection. Some series report 100% 5-year survival, and nearly all patients (96%) live to 10 years following surgery.6, 15 Furthermore, occasional examples of spontaneous regression have been well recognized.16, 17 Therefore, the treatment of choice for PA is gross total surgical resection.
PA can rarely undergo malignant transformation, which can be spontaneous or associated with radiation therapy.18, 19 Malignant transformation is characterized histologically by the presence of numerous mitoses and palisading necrosis. However, even these cases can be cured by surgery with or without adjuvant therapy as reported in a subset of patients.5 Since their prognosis has not been considered akin to glioblastoma, the 2007 WHO classification designated anaplastic (malignant) PA without a corresponding grade. It remains to be seen whether a separate grade for such anaplastic tumors is warranted.
6
Molecular Biology of Pilocytic Astrocytoma and the Importance of the MAPK Pathway A growing body of evidence has demonstrated a key role for the MAPK pathway on the biology of PA. The genetic association between Neurofibromatosis Type I (NF-1) and PA is well known, and patients with this condition typically develop bilateral optic nerve PAs.20 Patients with NF-1 have inactivation of the tumor suppressor gene NF1, which encodes neurofibromin, a negative regulator of RAS. Persistent activation of RAS leads to downstream activation of the mTOR pathway and transcription of genes involved in cellular proliferation.21, 22 While some studies reported spontaneous regression and a more indolent course for NF-1 patients compared to sporadic cases,23 a multi-institutional study of PA showed no difference in progression-free survival or overall survival between NF-1 associated and sporadic PAs.24 Nevertheless, the association between PA and NF-1 suggested a link between PA and the MAPK pathway, directing further studies to a careful examination of this pathway. The 1.9-MB gain at chromosome 7q34, resulting from a fusion between KIAA1549 and BRAF genes, was subsequently described by many authors.25-27 This fusion causes a deletion of the amino-terminal domain of BRAF and constitutive activation of its kinase activity.28-30 KIAA1549-BRAF fusion constitutes the most common molecular alteration in sporadic PA and is particularly common among posterior fossa tumors.11, 25, 27, 28, 31-34 Other molecular alterations in the BRAF gene have also been reported, including alternative fusion products,35, 36 rare BRAFV600E mutations,37 BRAF insertions,38 and KRAS mutations.9 How these genetic alterations correlate with tumor location and behavior is not entirely clear although all of them lead to downstream activation of proteins in the MEK/MAPK pathway. Mutations in BRAF have been reported in a host of other cancers
7
including melanomas, lung and gastric cancers, as well as benign lesions such as melanocytic nevi and colorectal polyps.39, 40
The presence of BRAF oncogene alterations and MEK/MAPK activation in PA raises the possibility that these tumors may also be subjected to oncogene-induced senescence (OIS), a key biological mechanism controlling tumor growth and behavior. Cellular senescence refers to the process whereby proliferating cells adopt a state of permanent cell-cycle arrest.41 Normal cells can undergo cellular senescence through oncogene overexpression, and activation of the MAPK pathway has been strongly associated with initiation of the OIS response.41-45 Therefore, OIS activation provides a molecular explanation for the long periods of dormancy and/or spontaneous regression observed in PA.46 Likewise, loss of NF1 leads to hyperactivation of the oncogene KRAS and downstream activation of the MAPK pathway, which can induce senescence through p16 activation.42 In fact, activation of p16 in PA provides further support for the suggestion that these tumors may be subject to OIS.11, 47 Furthermore, the loss of CDKN2A, the gene encoding p16, in PA is associated with worse clinical outcome, suggesting that an intact OIS response is crucial to the indolent biologic behavior in PA.47
The aforementioned studies suggest that variable activation of the MAPK pathway and OIS may explain the variations in biological behavior seen in PA. It remains to be determined which PAs are subject to OIS and which may abrogate this process and behave more aggressively. Correctly identifying this biological mechanism will be crucial to the design of more effective treatment protocols for PA.
8
Pros and Cons of Targeting the MAPK pathway While surgical resection is the treatment of choice for PA, patients with either inoperable disease or tumors not amenable to gross total resection frequently undergo chemotherapy and/or radiation.48 Currently, chemotherapy is the preferred treatment for children younger than 10 years of age because of the significant adverse impact of radiotherapy on neurocognitive development.49 Clinical trials advocate the use of combination chemotherapy with carboplatin and vincristine because they offer lower toxicity in comparison with other agents and regimens.49-51 Radiotherapy is sometimes recommended for older children and adults with subtotal resection or in cases of tumor progression.
One caveat of using radiotherapy to treat tumors with an activated OIS may be the introduction of additional mutations or genetic silencing within crucial checkpoints such as CDKN2A or TP53. Consequently, alterations in these genes may abrogate OIS and lead to tumor progression.52 In fact, some studies have associated anaplastic transformation of low-grade gliomas to prior radiotherapy.18, 19
Given the known molecular alterations in PA, specific inhibitors to kinases in the MAPK pathway could provide ideal targets in the future treatment of PA. Indeed, recent studies using AZD6244 (selumetinib), an extracellular inhibitor of kinase phosphorylation that targets the Ras/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, has demonstrated some promise.48 However, the MAPK pathway is complex, and the development of resistance to single inhibitor therapy represents a potential limitation to this approach.53-55 Furthermore, resistance to AZD6244 given as single-agent therapy has already been reported,56
9
potentially through alterations in MEK1 or Ras activation via PI3 kinase signaling. Rapamycin may provide a useful adjuvant agent in combination chemotherapy as demonstrated for the treatment of NF-1 children with low-grade glioma.57, 58 Salvage therapy with vinblastine alone could be used in pediatric patients with recurrent disease, so radiotherapy may be further delayed.59
Of note, the MAPK pathway has several important regulators, including sprouty family of proteins, Raf kinase inhibitor protein, and the dual-specific MAPK phosphatase.60-67 Because alterations in these factors could impact responsiveness to MAPK pathway inhibitors, designing effective therapies for PA may benefit from elucidating the role these proteins play on the biology of PA.
Guidelines for Treating Pilocytic Astrocytomas Several issues must be considered for successfully establishing effective therapies to PA. First, selection of the therapeutic approach should follow identification of the type of MAPK alteration. For example, a PA bearing the BRAFV600E mutation may benefit from therapy with vemurafenib, which specifically inhibits this mutated form of BRAF. Second, combination regimens would appear crucial for tumor eradication and to prevent the development of drug resistance. Third, balancing MAPK pathway inhibition with abrogation of OIS should be carefully considered to preserve an intact OIS. Certainly, inoperable tumors may require chemotherapy and/or radiotherapy as the first line of treatment. However, radiotherapy should be delayed as much as possible, especially when treating children and NF-1 patients.49-51 It is
10
critical to avoid overtreatment of PA, since aggressive therapy could cause more harm than good.68
11
REFERENCES 1. Bailey P, Cushing H. A classification of the tumors of the glioma group on a histogenetic basis with a correlated study of prognosis. Philadelphia, London: J.B. Lippincott Co; 1926. 2.
Zulch KJ. Histologic typing of tumours of the central nervous system. Vol 21. First Edition. Geneva, World Health Organization; 1979.
3.
Ringertz N, Nordenstam H. Cerebellar astrocytoma. J Neuropathol Exp Neurol. 10(4):343-367, 1951.
4.
Kleihues P, Burger PC, Scheithauer BW. Histologic typing of tumours of the central nervous system. Second Edition. Berlin, Germany: Springer-Verlag Berlin Heidelberg; 1993.
5.
Scheithauer BW, Hawkins C, Tihan T, VanderBerg SR, Burger PC. Pilocytic astrocytoma. In: Louis, DN, Cavenee, WK, Ohgaki, H, Wiestler, OD, eds. WHO classification of tumours of the central nervous system. 4th Edition. Lyon; 2007:14-21.
6.
Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 64(6):479-489, 2005.
7.
Tihan T, Fisher PG, Kepner JL, et al. Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J Neuropathol Exp Neurol. 58(10):1061-1068, 1999.
8.
Komotar RJ, Mocco J, Carson BS, et al. Pilomyxoid astrocytoma: a review. MedGenMed. 6(4):42, 2004.
9.
Forshew T, Tatevossian RG, Lawson AR, et al. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol. 218(2):172181, 2009.
10.
Parsa CF, Hoyt CS, Lesser RL, et al. Spontaneous regression of optic gliomas: thirteen cases documented by serial neuroimaging. Arch Ophthalmol. 119(4):516-529, 2001.
11.
Reis GF, Bloomer MM, Perry A, et al. Pilocytic astrocytomas of the optic nerve and their relation to pilocytic astrocytomas elsewhere in the central nervous system. Mod Pathol. 26(10):1279-87, 2013.
12.
Clark GB, Henry JM, McKeever PE. Cerebral pilocytic astrocytoma. Cancer. 56(5):1128-1133, 1985.
13.
Garcia DM, Fulling KH. Juvenile pilocytic astrocytoma of the cerebrum in adults. A distinctive neoplasm with favorable prognosis. J Neurosurg. 63(3):382-386, 1985.
12
14.
Forsyth PA, Shaw EG, Scheithauer BW, O'Fallon JR, Layton DD, Jr., Katzmann JA. Supratentorial pilocytic astrocytomas. A clinicopathologic, prognostic, and flow cytometric study of 51 patients. Cancer. 72(4):1335-1342, 1993.
15.
Fernandez C, Figarella-Branger D, Girard N, et al. Pilocytic astrocytomas in children: prognostic factors--a retrospective study of 80 cases. Neurosurgery. 53(3):544-553, 2003.
16.
Gunny RS, Hayward RD, Phipps KP, Harding BN, Saunders DE. Spontaneous regression of residual low-grade cerebellar pilocytic astrocytomas in children. Pediatr Radiol. 35(11):1086-1091, 2005.
17.
Legius E, Marchuk DA, Collins FS, Glover TW. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet. 3(2):122-126, 1993.
18.
Dirks PB, Jay V, Becker LE, et al. Development of anaplastic changes in low-grade astrocytomas of childhood. Neurosurgery. 34(1):68-78, 1994.
19.
Tomlinson FH, Scheithauer BW, Hayostek CJ, et al. The significance of atypia and histologic malignancy in pilocytic astrocytoma of the cerebellum: a clinicopathologic and flow cytometric study. J Child Neurol. 9(3):301-310, 1994.
20.
Lewis RA, Gerson LP, Axelson KA, Riccardi VM, Whitford RP. von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology. 91(8):929-935, 1984.
21.
Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1associated human and mouse brain tumors. Cancer Res. 65(7):2755-2760, 2005.
22.
Chen YH, Gutmann DH. The molecular and cell biology of pediatric low-grade gliomas. Oncogene. 33(16): 2019-26, 2014.
23.
Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg. 85(1):56-65, 1996.
24.
Tihan T, Ersen A, Qaddoumi I, et al. Pathologic characteristics of pediatric intracranial pilocytic astrocytomas and their impact on outcome in 3 countries: a multi-institutional study. Am J Surg Pathol. 36(1):43-55, 2012.
25.
Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol. Sep 67(9):878-887, 2008.
26.
Deshmukh H, Yeh TH, Yu J, et al. High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. Oncogene. 27(34):4745-4751, 2008.
13
27.
Pfister S, Janzarik WG, Remke M, et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 118(5):17391749, 2008.
28.
Jones DT, Kocialkowski S, Liu L, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 68(21):8673-8677, 2008.
29.
Ciampi R, Knauf JA, Kerler R, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest. 115(1):94-101, 2005.
30.
Tran NH, Wu X, Frost JA. B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. J Biol Chem. 280(16):16244-16253, 2005.
31.
Jacob K, Albrecht S, Sollier C, et al. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer. 101(4):722-733, 2009.
32.
Sievert AJ, Jackson EM, Gai X, et al. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol. 19(3):449-458, 2009.
33.
Yu J, Deshmukh H, Gutmann RJ, et al. Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology. 73(19):1526-1531, 2009.
34.
Rodriguez FJ, Ligon AH, Horkayne-Szakaly I, et al. BRAF Duplications and MAPK Pathway Activation Are Frequent in Gliomas of the Optic Nerve Proper. J Neuropathol Exp Neurol. 71(9):789-794, 2012.
35.
Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene. 28(20):2119-2123, 2009.
36.
Cin H, Meyer C, Herr R, et al. Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol. 121(6):763-774, 2011.
37.
Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 121(3):397-405, 2011.
38.
Eisenhardt AE, Olbrich H, Roring M, et al. Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma. Int J Cancer. 129(9):2297-2303, 2011.
14
39.
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 24(22):2463-2479, 2010.
40.
Minoo P, Jass JR. Senescence and serration: a new twist to an old tale. J Pathol. 210(2):137-140, 2006.
41.
Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 8(9):729-740, 2007.
42.
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 88(5):593-602, 1997.
43.
Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12(19):3008-3019, 1998.
44.
Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell death-apoptosis, autophagy and senescence. FEBS J. 277(1):2-21, 2010.
45.
Evan GI, d'Adda di Fagagna F. Cellular senescence: hot or what? Curr Opin Genet Dev. 19(1):25-31, 2009.
46.
Borit A, Richardson EP, Jr. The biological and clinical behaviour of pilocytic astrocytomas of the optic pathways. Brain. 105(Pt 1):161-187, 1982.
47.
Raabe EH, Lim KS, Kim JM, et al. BRAF activation induces transformation and then senescence in human neural stem cells: a pilocytic astrocytoma model. Clin Cancer Res. 17(11):3590-3599, 2011.
48.
Sadighi Z, Slopis J. Pilocytic astrocytoma: a disease with evolving molecular heterogeneity. J Child Neurol. 28(5):625-632, 2013.
49.
Perilongo G. Considerations on the role of chemotherapy and modern radiotherapy in the treatment of childhood low grade glioma. J Neurooncol. 75(3):301-307, 2005.
50.
Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol. 30(21):2641-2647, 2012.
51.
Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg. 86(5):747-754, 1997.
52.
Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol. 14(6):777-789, 2012.
15
53.
Wee S, Jagani Z, Xiang KX, et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 69(10):4286-4293, 2009.
54.
Kolb EA, Gorlick R, Houghton PJ, et al. Initial testing (stage 1) of AZD6244 (ARRY142886) by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 55(4):668677, 2010.
55.
Emery CM, Vijayendran KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 106(48):20411-20416, 2009.
56.
Lafay-Cousin L, Holm S, Qaddoumi I, et al. Weekly vinblastine in pediatric low-grade glioma patients with carboplatin allergic reaction. Cancer. 103(12):2636-2642, 2005.
57.
Greger JG, Eastman SD, Zhang V, et al. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther. 11(4):909-920, 2012.
58.
Yalon M, Rood B, MacDonald TJ, et al. A feasibility and efficacy study of rapamycin and erlotinib for recurrent pediatric low-grade glioma (LGG). Pediatr Blood Cancer. 60(1):71-76, 2013.
59.
Bouffet E, Jakacki R, Goldman S, et al. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol. 30(12):1358-1363, 2012.
60.
Courtois-Cox S, Genther Williams SM, Reczek EE, et al. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 10(6):459-472, 2006.
61.
Murphy T, Hori S, Sewell J, Gnanapragasam VJ. Expression and functional role of negative signalling regulators in tumour development and progression. Int J Cancer. 127(11):2491-2499, 2010.
62.
Matheny SA, Chen C, Kortum RL, Razidlo GL, Lewis RE, White MA. Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature. 427(6971):256-260, 2004.
63.
Yeung K, Janosch P, McFerran B, et al. Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol Cell Biol. 20(9):3079-3085, 2000.
64.
Owens DM, Keyse SM. Differential regulation of MAP kinase signalling by dualspecificity protein phosphatases. Oncogene. 26(22):3203-3213, 2007.
65.
Kim HJ, Bar-Sagi D. Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol. 5(6):441-450, 2004.
66.
Boutros T, Chevet E, Metrakos P. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev. 60(3):261-310, 2008. 16
67.
Kwak HJ, Kim YJ, Chun KR, et al. Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene. 30(21):2433-2442, 2011.
68.
Burger PC, Scheithauer BW, Lee RR, O'Neill BP. An interdisciplinary approach to avoid the overtreatment of patients with central nervous system lesions. Cancer. 80(11):20402046, 1997.
17
