What's New in Grade II and Grade III Gliomas?

Abstract

The majority of World Health Organization grade II and grade III gliomas harbor heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1), and tumors with an IDH wild-type status show molecular features of a glioblastoma and simply may constitute a separate disease entity. This discovery has led to a profound shift in the way that gliomas are classified and, consequently, how treatment decisions are made. We will review the current understanding of IDH-mutant gliomagenesis and the preclinical models being used to investigate the underlying biology of these tumors and to explore new therapeutic options for these patients. We further summarize the results of recent pivotal trials addressing treatment of grade II and grade III gliomas and highlight promising IDH-mutant-specific therapies on the horizon.

Keywords

isocitrate dehydrogenase - 2-hydroxyglutarate - 1p/19q co-deletion - CATNON - CODEL

• References

• 1 Louis DN, Ohgaki H, Wiestler O. , et al. WHO Classification of Tumours of the Central Nervous System, Revised. 4th ed. Lyon: International Agency for Research on Cancer; 2016
• 2 Reuss DE, Kratz A, Sahm F. , et al. Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neuropathol 2015; 130 (03) 407-417
• 3 Yan H, Parsons DW, Jin G. , et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360 (08) 765-773
• 4 Hartmann C, Hentschel B, Wick W. , et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol 2010; 120 (06) 707-718
• 5 Olar A, Wani KM, Alfaro-Munoz KD. , et al. IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas. Acta Neuropathol 2015; 129 (04) 585-596
• 6 von Deimling A, Louis DN, von Ammon K, Petersen I, Wiestler OD, Seizinger BR. Evidence for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas. Cancer Res 1992; 52 (15) 4277-4279
• 7 Kraus JA, Koopmann J, Kaskel P. , et al. Shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligodendroglioma and oligoastrocytoma. J Neuropathol Exp Neurol 1995; 54 (01) 91-95
• 8 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 rates of self-renewal. Proc Natl Acad Sci U S A 2013; 110 (15) 6021-6026
• 9 Jiao Y, Killela PJ, Reitman ZJ. , et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 2012; 3 (07) 709-722
• 10 Eckel-Passow JE, Lachance DH, Molinaro AM. , et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 2015; 372 (26) 2499-2508
• 11 Brat DJ, Verhaak RG, Aldape KD. , et al; Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015; 372 (26) 2481-2498
• 12 Dang L, White DW, Gross S. , et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462 (7274): 739-744
• 13 Xu W, Yang H, Liu Y. , et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19 (01) 17-30
• 14 Dunn GP, Andronesi OC, Cahill DP. From genomics to the clinic: biological and translational insights of mutant IDH1/2 in glioma. Neurosurg Focus 2013; 34 (02) E2
• 15 Metallo CM, Gameiro PA, Bell EL. , et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2011; 481 (7381): 380-384
• 16 Grassian AR, Parker SJ, Davidson SM. , et al. IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Res 2014; 74 (12) 3317-3331
• 17 Tateishi K, Wakimoto H, Iafrate AJ. , et al. Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 2015; 28 (06) 773-784
• 18 Parsons DW, Jones S, Zhang X. , et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321 (5897): 1807-1812
• 19 Tirosh I, Venteicher AS, Hebert C. , et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature 2016; 539 (7628): 309-313
• 20 Venteicher AS, Tirosh I, Hebert C. , et al. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science 2017; 355 (6332): 355
• 21 Johnson BE, Mazor T, Hong C. , et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 2014; 343 (6167): 189-193
• 22 Luchman HA, Stechishin OD, Dang NH. , et al. An in vivo patient-derived model of endogenous IDH1-mutant glioma. Neuro Oncol 2012; 14 (02) 184-191
• 23 Wakimoto H, Tanaka S, Curry WT. , et al. Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas. Clin Cancer Res 2014; 20 (11) 2898-2909
• 24 Lenting K, Verhaak R, Ter Laan M, Wesseling P, Leenders W. Glioma: experimental models and reality. Acta Neuropathol 2017; 133 (02) 263-282
• 25 Navis AC, Niclou SP, Fack F. , et al. Increased mitochondrial activity in a novel IDH1-R132H mutant human oligodendroglioma xenograft model: in situ detection of 2-HG and α-KG. Acta Neuropathol Commun 2013; 1: 18
• 26 Rohle D, Popovici-Muller J, Palaskas N. , et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 2013; 340 (6132): 626-630
• 27 Klink B, Miletic H, Stieber D. , et al. A novel, diffusely infiltrative xenograft model of human anaplastic oligodendroglioma with mutations in FUBP1, CIC, and IDH1. PLoS One 2013; 8 (03) e59773
• 28 Ohba S, Mukherjee J, See WL, Pieper RO. Mutant IDH1-driven cellular transformation increases RAD51-mediated homologous recombination and temozolomide resistance. Cancer Res 2014; 74 (17) 4836-4844
• 29 Ohba S, Mukherjee J, Johannessen TC. , et al. Mutant IDH1 expression drives TERT promoter reactivation as part of the cellular transformation process. Cancer Res 2016; 76 (22) 6680-6689
• 30 Johannessen TA, Mukherjee J, Viswanath P. , et al. Rapid conversion of mutant IDH1 from driver to passenger in a model of human gliomagenesis. Mol Cancer Res 2016; 14 (10) 976-983
• 31 Sulkowski PL, Corso CD, Robinson ND. , et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med 2017; 9 (375) 9
• 32 Sasaki M, Knobbe CB, Itsumi M. , et al. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev 2012; 26 (18) 2038-2049
• 33 Bardella C, Al-Dalahmah O, Krell D. , et al. Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis. Cancer Cell 2016; 30 (04) 578-594
• 34 Kros JM, Gorlia T, Kouwenhoven MC. , et al. Panel review of anaplastic oligodendroglioma from European Organization For Research and Treatment of Cancer Trial 26951: assessment of consensus in diagnosis, influence of 1p/19q loss, and correlations with outcome. J Neuropathol Exp Neurol 2007; 66 (06) 545-551
• 35 Beiko J, Suki D, Hess KR. , et al. IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection. Neuro Oncol 2014; 16 (01) 81-91
• 36 van den Bent MJ. Chemotherapy for low-grade glioma: when, for whom, which regimen?. Curr Opin Neurol 2015; 28 (06) 633-938
• 37 van den Bent MJ, Afra D, de Witte O. , et al; EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 2005; 366 (9490): 985-990
• 38 Buckner JC, Shaw EG, Pugh SL. , et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 2016; 374 (14) 1344-1355
• 39 Baumert BG, Hegi ME, van den Bent MJ. , et al. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 2016; 17 (11) 1521-1532
• 40 Reijneveld JC, Taphoorn MJ, Coens C. , et al. Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 2016; 17 (11) 1533-1542
• 41 Weller M, van den Bent M, Tonn JC. , et al; European Association for Neuro-Oncology (EANO) Task Force on Gliomas. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol 2017; 18 (06) e315-e329
• 42 Wick W, Roth P, Hartmann C. , et al; Neurooncology Working Group (NOA) of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol 2016; 18 (11) 1529-1537
• 43 Cairncross G, Wang M, Shaw E. , et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 2013; 31 (03) 337-343
• 44 Cairncross JG, Wang M, Jenkins RB. , et al. Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH. J Clin Oncol 2014; 32 (08) 783-790
• 45 van den Bent MJ, Brandes AA, Taphoorn MJ. , et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 2013; 31 (03) 344-350
• 46 van den Bent MJ, Erridge S, Vogelbaum MA. , et al. Results of the interim analysis of the EORTC randomized phase III CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q co-deletion: an intergroup trial. J Clin Oncol 2016; 34: LBA2000
• 47 Wick W, Weller M, van den Bent M. , et al. MGMT testing--the challenges for biomarker-based glioma treatment. Nat Rev Neurol 2014; 10 (07) 372-385
• 48 Jaeckle K, Vogelbaum M, Ballman K. , et al. CODEL (Alliance-N0577; EORTC-26081/22086; NRG-1071; NCIC-CEC-2): phase III randomized study of RT vs. RT+TMZ vs. TMZ for newly diagnosed 1p/19q-codeleted anaplastic oligodendroglial tumors. Analysis of patients treated on the original protocol design. Neurology 2016; 86 (16 Supplement): Abstract PL02.005
• 49 Massett H, Jaeckle KA, Dilts DM. , et al. Rapid online feedback to improve clinical trial accrual: CODEL anaplastic glioma (AG) (NCCTG/Alliance N0577) as a model. J Clin Oncol 2013; 31: 1596
• 50 Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 2009; 174 (04) 1149-1153
• 51 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
• 52 Juratli TA, Kirsch M, Robel K. , et al. IDH mutations as an early and consistent marker in low-grade astrocytomas WHO grade II and their consecutive secondary high-grade gliomas. J Neurooncol 2012; 108 (03) 403-410
• 53 Lu C, Ward PS, Kapoor GS. , et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012; 483 (7390): 474-478
• 54 Agios Announces Phase 1 Data from Dose Expansion Cohorts of AG-120 in Patients with IDH1 Mutant Positive Glioma and Chondrosarcoma [news release]. Cambridge, MA. Global Newswire; November 18, 2016. http://investor.agios.com/phoenix.zhtml? c=251862&p=irol-newsArticle&ID=2223601 . Accessed on June 9, 2017
• 55 Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol 2016; 27 (04) 599-608
• 56 Stein EM, DiNardo CD, Pollyea DA. , et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017; 130 (06) 722-731
• 57 Turcan S, Rohle D, Goenka A. , et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012; 483 (7390): 479-483
• 58 Turcan S, Fabius AW, Borodovsky A. , et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine. Oncotarget 2013; 4 (10) 1729-1736
• 59 Borodovsky A, Salmasi V, Turcan S. , et al. 5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft. Oncotarget 2013; 4 (10) 1737-1747
• 60 Fathi AT, Wander SA, Faramand R, Emadi A. Biochemical, epigenetic, and metabolic approaches to target IDH mutations in acute myeloid leukemia. Semin Hematol 2015; 52 (03) 165-171
• 61 Schumacher T, Bunse L, Pusch S. , et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 2014; 512 (7514): 324-327
• 62 Pellegatta S, Valletta L, Corbetta C. , et al. Effective immuno-targeting of the IDH1 mutation R132H in a murine model of intracranial glioma. Acta Neuropathol Commun 2015; 3: 4
• 63 Snyder A, Wolchok JD. Successful treatment of a patient with glioblastoma and a germline POLE mutation: where next?. Cancer Discov 2016; 6 (11) 1210-1211
• 64 Cahill DP, Levine KK, Betensky RA. , et al. Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res 2007; 13 (07) 2038-2045
• 65 Cahill DP, Codd PJ, Batchelor TT, Curry WT, Louis DN. MSH6 inactivation and emergent temozolomide resistance in human glioblastomas. Clin Neurosurg 2008; 55: 165-171
• 66 van Thuijl HF, Mazor T, Johnson BE. , et al. Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. Acta Neuropathol 2015; 129 (04) 597-607