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Semin Neurol 2018; 38(01): 050-061
DOI: 10.1055/s-0038-1623534
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

New Directions in the Treatment of Glioblastoma

Zachary J. Reitman
1   Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
2   Harvard Radiation Oncology Program, Boston, Massachusetts
,
Frank Winkler
3   Neurology Clinic & German Consortium for Translational Cancer Research (DKTK), Heidelberg University Medical Center & DKFZ, Heidelberg, Germany
,
Andrew E. H. Elia
1   Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
2   Harvard Radiation Oncology Program, Boston, Massachusetts
4   Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
› Author Affiliations
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Publication History

Publication Date:
16 March 2018 (online)

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Abstract

Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. The current standard of care for GBM is maximal resection followed by postoperative radiation with concomitant and adjuvant temozolomide. Despite this multimodality treatment, the median survival for GBM remains marginally better than 1 year. In the past decade, genome-wide analyses have uncovered new molecular features of GBM that have refined its classification and provided new insights into the molecular basis for GBM pathogenesis. Here, we review these molecular features and discuss major clinical trials that have recently defined the field. We describe genetic alterations in isocitrate dehydrogenase, ATRX, the telomerase promoter, and histone H3 variants that promote GBM tumorigenesis and have altered GBM categorization. We also discuss intratumoral genetic heterogeneity as one explanation for therapeutic failures and explain how ultra-long extensions of glioma cells, called tumor microtubes, mediate therapeutic resistance. These findings provide new insights into GBM biology and offer hope for the development of next-generation therapies.

Keywords

glioblastoma - WHO grade IV - IDH - TERT - ATRX - nanotubes
 

  • References

  • 1 Ostrom QT, Gittleman H, Xu J. , et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009-2013. Neuro Oncol 2016; 18 (05) (Suppl. 05) v1-v75
    CrossrefPubMedGoogle Scholar
  • 2 Ron E, Modan B, Boice Jr JD. , et al. Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 1988; 319 (16) 1033-1039
    CrossrefPubMedGoogle Scholar
  • 3 Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA 2013; 310 (17) 1842-1850
    CrossrefPubMedGoogle Scholar
  • 4 Melin BS, Barnholtz-Sloan JS, Wrensch MR. , et al; GliomaScan Consortium. Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors. Nat Genet 2017; 49 (05) 789-794
    CrossrefPubMedGoogle Scholar
  • 5 Parsons DW, Jones S, Zhang X. , et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321 (5897): 1807-1812
    CrossrefPubMedGoogle Scholar
  • 6 Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008; 455 (7216): 1061-1068
    CrossrefPubMedGoogle Scholar
  • 7 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 (01) 98-110
    CrossrefPubMedGoogle Scholar
  • 8 Brennan CW, Verhaak RG, McKenna A. , et al; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell 2013; 155 (02) 462-477
    CrossrefPubMedGoogle Scholar
  • 9 Brown TJ, Brennan MC, Li M. , et al. Association of the extent of resection with survival in glioblastoma: a systematic review and meta-analysis. JAMA Oncol 2016; 2 (11) 1460-1469
    CrossrefPubMedGoogle Scholar
  • 10 Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006; 7 (05) 392-401
    CrossrefPubMedGoogle Scholar
  • 11 Walker MD, Alexander Jr E, Hunt WE. , et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 1978; 49 (03) 333-343
    CrossrefPubMedGoogle Scholar
  • 12 Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 1979; 5 (10) 1725-1731
    CrossrefPubMedGoogle Scholar
  • 13 Bleehen NM, Stenning SP. ; The Medical Research Council Brain Tumour Working Party. A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. Br J Cancer 1991; 64 (04) 769-774
    CrossrefPubMedGoogle Scholar
  • 14 Nelson DF, Diener-West M, Horton J, Chang CH, Schoenfeld D, Nelson JS. Combined modality approach to treatment of malignant gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group. NCI Monogr 1988; (06) 279-284
    PubMedGoogle Scholar
  • 15 Souhami L, Seiferheld W, Brachman D. , et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 2004; 60 (03) 853-860
    CrossrefPubMedGoogle Scholar
  • 16 Corso CD, Bindra RS, Mehta MP. The role of radiation in treating glioblastoma: here to stay. J Neurooncol 2017; 134 (03) 479-485
    CrossrefPubMedGoogle Scholar
  • 17 Stupp R, Hegi ME, Mason WP. , et al; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10 (05) 459-466
    CrossrefPubMedGoogle Scholar
  • 18 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
    CrossrefPubMedGoogle Scholar
  • 19 Gilbert MR, Dignam JJ, Armstrong TS. , et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014; 370 (08) 699-708
    CrossrefPubMedGoogle Scholar
  • 20 Chinot OL, Wick W, Mason W. , et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 2014; 370 (08) 709-722
    CrossrefPubMedGoogle Scholar
  • 21 Stupp R, Hegi ME, Gorlia T. , et al; European Organisation for Research and Treatment of Cancer (EORTC); Canadian Brain Tumor Consortium; CENTRIC study team. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15 (10) 1100-1108
    CrossrefPubMedGoogle Scholar
  • 22 Valtonen S, Timonen U, Toivanen P. , et al. Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 1997; 41 (01) 44-48 , discussion 48–49
    CrossrefPubMedGoogle Scholar
  • 23 Westphal M, Hilt DC, Bortey E. , et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 2003; 5 (02) 79-88
    CrossrefPubMedGoogle Scholar
  • 24 Stupp R, Taillibert S, Kanner A. , et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma. JAMA 2017; 318 (23) 2306-2316
    CrossrefPubMedGoogle Scholar
  • 25 Mehta M, Wen P, Nishikawa R, Reardon D, Peters K. Critical review of the addition of tumor treating fields (TTFields) to the existing standard of care for newly diagnosed glioblastoma patients. Crit Rev Oncol Hematol 2017; 111: 60-65
    CrossrefPubMedGoogle Scholar
  • 26 Vuorinen V, Hinkka S, Färkkilä M, Jääskeläinen J. Debulking or biopsy of malignant glioma in elderly people - a randomised study. Acta Neurochir (Wien) 2003; 145 (01) 5-10
    CrossrefPubMedGoogle Scholar
  • 27 Keime-Guibert F, Chinot O, Taillandier L. , et al; Association of French-Speaking Neuro-Oncologists. Radiotherapy for glioblastoma in the elderly. N Engl J Med 2007; 356 (15) 1527-1535
    CrossrefPubMedGoogle Scholar
  • 28 Roa W, Brasher PM, Bauman G. , et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 2004; 22 (09) 1583-1588
    CrossrefPubMedGoogle Scholar
  • 29 Roa W, Kepka L, Kumar N. , et al. International Atomic Energy Agency randomized phase III study of radiation therapy in elderly and/or frail patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 2015; 33 (35) 4145-4150
    CrossrefPubMedGoogle Scholar
  • 30 Wick W, Platten M, Meisner C. , et al; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 2012; 13 (07) 707-715
    CrossrefPubMedGoogle Scholar
  • 31 Malmström A, Grønberg BH, Marosi C. , et al; Nordic Clinical Brain Tumour Study Group (NCBTSG). Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 2012; 13 (09) 916-926
    CrossrefPubMedGoogle Scholar
  • 32 Perry JR, Laperriere N, O'Callaghan CJ. , et al; Trial Investigators. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 2017; 376 (11) 1027-1037
    CrossrefPubMedGoogle Scholar
  • 33 Seystahl K, Wick W, Weller M. Therapeutic options in recurrent glioblastoma--an update. Crit Rev Oncol Hematol 2016; 99: 389-408
    CrossrefPubMedGoogle Scholar
  • 34 Fogh SE, Andrews DW, Glass J. , et al. Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol 2010; 28 (18) 3048-3053
    CrossrefPubMedGoogle Scholar
  • 35 Park JK, Hodges T, Arko L. , et al. Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol 2010; 28 (24) 3838-3843
    CrossrefPubMedGoogle Scholar
  • 36 Weller M, Tabatabai G, Kästner B. , et al; DIRECTOR Study Group. MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR trial. Clin Cancer Res 2015; 21 (09) 2057-2064
    CrossrefPubMedGoogle Scholar
  • 37 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
    CrossrefPubMedGoogle Scholar
  • 38 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 (05) 740-745
    CrossrefPubMedGoogle Scholar
  • 39 Taal W, Oosterkamp HM, Walenkamp AM. , et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 2014; 15 (09) 943-953
    CrossrefPubMedGoogle Scholar
  • 40 Wick W, Brandes AA, Gorlia T. , et al. LB-05 phase III trial exploring the combination of bevacizumab and lomustine in patients with first recurrence of a glioblastoma: the EORTC 26101 trial. Neuro Oncol 2015; 17 (05) v1
    CrossrefPubMedGoogle Scholar
  • 41 Wick W, Puduvalli VK, Chamberlain MC. , et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 2010; 28 (07) 1168-1174
    CrossrefPubMedGoogle Scholar
  • 42 Batchelor TT, Mulholland P, Neyns B. , et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 2013; 31 (26) 3212-3218
    CrossrefPubMedGoogle Scholar
  • 43 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
    CrossrefPubMedGoogle Scholar
  • 44 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 2011; 121 (03) 397-405
    CrossrefPubMedGoogle Scholar
  • 45 Hatae R, Hata N, Suzuki SO. , et al. A comprehensive analysis identifies BRAF hotspot mutations associated with gliomas with peculiar epithelial morphology. Neuropathology 2017; 37 (03) 191-199
    CrossrefPubMedGoogle Scholar
  • 46 Alexandrescu S, Korshunov A, Lai SH. , et al. Epithelioid glioblastomas and anaplastic epithelioid pleomorphic xanthoastrocytomas--same entity or first cousins?. Brain Pathol 2016; 26 (02) 215-223
    CrossrefPubMedGoogle Scholar
  • 47 Hyman DM, Puzanov I, Subbiah V. , et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 2015; 373 (08) 726-736
    CrossrefPubMedGoogle Scholar
  • 48 Bhat KPL, Balasubramaniyan V, Vaillant B. , et al. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell 2013; 24 (03) 331-346
    CrossrefPubMedGoogle Scholar
  • 49 Sandmann T, Bourgon R, Garcia J. , et al. Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first-line radiotherapy and temozolomide: retrospective analysis of the AVAglio trial. J Clin Oncol 2015; 33 (25) 2735-2744
    CrossrefPubMedGoogle Scholar
  • 50 Patel AP, Tirosh I, Trombetta JJ. , et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014; 344 (6190): 1396-1401
    CrossrefPubMedGoogle Scholar
  • 51 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 (05) 510-522
    CrossrefPubMedGoogle Scholar
  • 52 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
    CrossrefPubMedGoogle Scholar
  • 53 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
    CrossrefPubMedGoogle Scholar
  • 54 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
    CrossrefPubMedGoogle Scholar
  • 55 Yan H, Parsons DW, Jin G. , et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360 (08) 765-773
    CrossrefPubMedGoogle Scholar
  • 56 Louis DN, Perry A, Reifenberger G. , et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131 (06) 803-820
    CrossrefPubMedGoogle Scholar
  • 57 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
    CrossrefPubMedGoogle Scholar
  • 58 Dang L, White DW, Gross S. , et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462 (7274): 739-744
    CrossrefPubMedGoogle Scholar
  • 59 Han CH, Batchelor TT. Isocitrate dehydrogenase mutation as a therapeutic target in gliomas. Linchuang Zhongliuxue Zazhi 2017; 6 (03) 33
    PubMedGoogle Scholar
  • 60 Losman JA, Kaelin Jr WG. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 2013; 27 (08) 836-852
    CrossrefPubMedGoogle Scholar
  • 61 Reifenberger G, Wirsching HG, Knobbe-Thomsen CB, Weller M. Advances in the molecular genetics of gliomas - implications for classification and therapy. Nat Rev Clin Oncol 2017; 14 (07) 434-452
    CrossrefPubMedGoogle Scholar
  • 62 Bell RJ, Rube HT, Kreig A. , et al. Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science 2015; 348 (6238): 1036-1039
    CrossrefPubMedGoogle Scholar
  • 63 Hakin-Smith V, Jellinek DA, Levy D. , et al. Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme. Lancet 2003; 361 (9360): 836-838
    CrossrefPubMedGoogle Scholar
  • 64 Lazzerini-Denchi E, Sfeir A. Stop pulling my strings - what telomeres taught us about the DNA damage response. Nat Rev Mol Cell Biol 2016; 17 (06) 364-378
    CrossrefPubMedGoogle Scholar
  • 65 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
    CrossrefPubMedGoogle Scholar
  • 66 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
    PubMedGoogle Scholar
  • 67 Schwartzentruber J, Korshunov A, Liu XY. , et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012; 482 (7384): 226-231
    CrossrefPubMedGoogle Scholar
  • 68 Flynn RL, Cox KE, Jeitany M. , et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 2015; 347 (6219): 273-277
    CrossrefPubMedGoogle Scholar
  • 69 Wu G, Broniscer A, McEachron TA. , et al; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 2012; 44 (03) 251-253
    CrossrefPubMedGoogle Scholar
  • 70 Solomon DA, Wood MD, Tihan T. , et al. Diffuse midline gliomas with histone H3-K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol 2016; 26 (05) 569-580
    CrossrefPubMedGoogle Scholar
  • 71 Sturm D, Witt H, Hovestadt V. , et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 2012; 22 (04) 425-437
    CrossrefPubMedGoogle Scholar
  • 72 Bender S, Tang Y, Lindroth AM. , et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 2013; 24 (05) 660-672
    CrossrefPubMedGoogle Scholar
  • 73 Lewis PW, Müller MM, Koletsky MS. , et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 2013; 340 (6134): 857-861
    CrossrefPubMedGoogle Scholar
  • 74 Grasso CS, Tang Y, Truffaux N. , et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 2015; 21 (06) 555-559
    CrossrefPubMedGoogle Scholar
  • 75 Hashizume R, Andor N, Ihara Y. , et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 2014; 20 (12) 1394-1396
    CrossrefPubMedGoogle Scholar
  • 76 Zadeh G, Aldape K. ACVR1 mutations and the genomic landscape of pediatric diffuse glioma. Nat Genet 2014; 46 (05) 421-422
    CrossrefPubMedGoogle Scholar
  • 77 Zhang L, Chen LH, Wan H. , et al. Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nat Genet 2014; 46 (07) 726-730
    CrossrefPubMedGoogle Scholar
  • 78 Parker NR, Khong P, Parkinson JF, Howell VM, Wheeler HR. Molecular heterogeneity in glioblastoma: potential clinical implications. Front Oncol 2015; 5: 55
    PubMedGoogle Scholar
  • 79 Snuderl M, Fazlollahi L, Le LP. , et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 2011; 20 (06) 810-817
    CrossrefPubMedGoogle Scholar
  • 80 Szerlip NJ, Pedraza A, Chakravarty D. , et al. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci U S A 2012; 109 (08) 3041-3046
    CrossrefPubMedGoogle Scholar
  • 81 Brown PD, Krishnan S, Sarkaria JN. , et al; North Central Cancer Treatment Group Study N0177. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol 2008; 26 (34) 5603-5609
    CrossrefPubMedGoogle Scholar
  • 82 Chakravarti A, Wang M, Robins HI. , et al. RTOG 0211: a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients. Int J Radiat Oncol Biol Phys 2013; 85 (05) 1206-1211
    CrossrefPubMedGoogle Scholar
  • 83 Weller M. , et al. ACT IV: an international, double-blind, phase 3 trial of rindopepimut in newly diagnosed, EGFRvIII-expressing glioblastoma. Neuro Oncol 2016; 18 (06) vi17-vi18
    PubMedGoogle Scholar
  • 84 Nikbakht H, Panditharatna E, Mikael LG. , et al. Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma. Nat Commun 2016; 7: 11185
    CrossrefPubMedGoogle Scholar
  • 85 Brastianos PK, Nayyar N, Rosebrock D. , et al. Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens. NPJ Oncology 2017; 1: 33
    PubMedGoogle Scholar
  • 86 Osswald M, Jung E, Sahm F. , et al. Brain tumour cells interconnect to a functional and resistant network. Nature 2015; 528 (7580): 93-98
    PubMedGoogle Scholar
  • 87 Osswald M, Solecki G, Wick W, Winkler F. A malignant cellular network in gliomas: potential clinical implications. Neuro Oncol 2016; 18 (04) 479-485
    CrossrefPubMedGoogle Scholar
  • 88 Weil S, Osswald M, Solecki G. , et al. Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas. Neuro Oncol 2017; 19 (10) 1316-1326
    CrossrefPubMedGoogle Scholar
  • 89 Jung E, Osswald M, Blaes J. , et al. Tweety-homolog 1 drives brain colonization of gliomas. J Neurosci 2017; 37 (29) 6837-6850
    CrossrefPubMedGoogle Scholar
  • 90 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
    CrossrefPubMedGoogle Scholar
  • 91 Lee EQ, Kaley TJ, Duda DG. , et al. A multicenter, phase II, randomized, noncomparative clinical trial of radiation and temozolomide with or without vandetanib in newly diagnosed glioblastoma patients. Clin Cancer Res 2015; 21 (16) 3610-3618
    CrossrefPubMedGoogle Scholar
  • 92 Reitman ZJ, Duncan CG, Poteet E. , et al. Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. J Biol Chem 2014; 289 (34) 23318-23328
    CrossrefPubMedGoogle Scholar
  • 93 Reitman ZJ, Jin G, Karoly ED. , et al. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci U S A 2011; 108 (08) 3270-3275
    CrossrefPubMedGoogle Scholar
  • 94 Tateishi K, Wakimoto H, Iafrate AJ. , et al. Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 2015; 28 (06) 773-784
    CrossrefPubMedGoogle Scholar
  • 95 Cloughesy TF, Cavenee WK, Mischel PS. Glioblastoma: from molecular pathology to targeted treatment. Annu Rev Pathol 2014; 9: 1-25
    CrossrefPubMedGoogle Scholar
  • 96 Reardon DA, Wen PY, Wucherpfennig KW, Sampson JH. Immunomodulation for glioblastoma. Curr Opin Neurol 2017; 30 (03) 361-369
    CrossrefPubMedGoogle Scholar
  • 97 Alexandrov LB, Nik-Zainal S, Wedge DC. , et al; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain. Signatures of mutational processes in human cancer. Nature 2013; 500 (7463): 415-421
    CrossrefPubMedGoogle Scholar
  • 98 Miller TE, Liau BB, Wallace LC. , et al. Transcription elongation factors represent in vivo cancer dependencies in glioblastoma. Nature 2017; 547 (7663): 355-359
    CrossrefPubMedGoogle Scholar
  • 99 Alexander BM, Cloughesy TF. Adult glioblastoma. J Clin Oncol 2017; 35 (21) 2402-2409
    CrossrefPubMedGoogle Scholar
  • 100 Wick A, Kessler T, Elia AEH. , et al. Glioblastoma in the elderly: solid conclusions built on shifting sand?. Neuro Oncol 2017
    PubMedGoogle Scholar
  • 101 Bjerke L, Mackay A, Nandhabalan M. , et al. Histone H3.3. mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discov 2013; 3 (05) 512-519
    CrossrefPubMedGoogle Scholar