Abstract
SUMMARY:
In the last few decades, we have seen significant advances in brain imaging, which have resulted in more detailed anatomic and functional localization of gliomas in relation to the eloquent cortex, as well as improvements in microsurgical techniques and enhanced delivery of adjuvant stereotactic radiation. While these advancements have led to a relatively modest improvement in clinical outcomes for patients with malignant gliomas, much more work remains to be done. As with other types of cancer, we are now rapidly moving past the era of histopathology dictating treatment for brain tumors and into the realm of molecular diagnostics and associated targeted therapies, specifically based on the genomic architecture of individual gliomas. In this review, we discuss the current era of molecular glioma characterization and how these profiles will allow for individualized, patient-specific targeted treatments.
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
References
- 1 CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2008. CBTRUS, Hinsdale, IL, USA (2012).
- 2 . Epidemiology of brain tumors. Neurol Clin. 25, 867–890 (2007).
- 3 . The 2007 WHO classification of tumors of the central nervous system – what has changed? Curr. Opin. Neurol. 21, 720–727 (2008).
- 4 . The 2007 Revised World Health Organization (WHO) Classification of Tumours of the Central Nervous System: newly codified entities. Brain Pathol. 17, 304–307 (2007).
- 5 Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).
- 6 . The neurobiology of gliomas: from cell biology to the development of therapeutic approaches. Nat. Rev. Neurosci. 12, 495–508 (2011). • Good complimentary review detailing molecular pathways in gliomas and potential therapeutic targets.
- 7 Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin. Cancer Res. 16, 2443–2449 (2010).
- 8 Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat. Genet. 45, 602–612 (2013). •• Landmark paper identifying multiple new genetic alterations in low-grade gliomas, including BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX.
- 9 . Current treatment of low grade gliomas. Memo. 5, 223–227 (2012).
- 10 IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012). • IDH1 mutation is responsible for epigenetic methylation.
- 11 DNA methylation profiles of long- and short-term glioblastoma survivors. Epigenetics 8, 149–156 (2013).
- 12 Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333, 1453–1455 (2011). • Specific genes mutated in oligodendrogliomas besides the well-known 1p/19q mutation.
- 13 . IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma. Neuro Oncol. 15, 1114–1126 (2013).
- 14 . Relative survival of patients with supratentorial low-grade gliomas. Neuro Oncol. 14, 1062–1069 (2012).
- 15 Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 21, 2683–2710 (2007).
- 16 . Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J. Neuropathol. Exp. Neurol. 64, 479–489 (2005).
- 17 . CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol. 14(Suppl. 5), v1–v49 (2012).
- 18 Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008). •• Glioblastoma has key mutations in MGMT, TP53, ERB and PI3K pathways.
- 19 et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012). •• New mutations identified in histone and epigenetic remodeling systems in glioblastoma (GBM). This paper helped pave the way that mutations in GBM go beyond just mutations in the genetic structure and instead stretch into the epigenetic realm.
- 20 Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).
- 21 . Genetic pathways to primary and secondary glioblastoma. Am. J. Pathol. 170, 1445–1453 (2007).
- 22 Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 17, 98–110 (2010).
- 23 . Therapeutic targeting of EGFR-activated metabolic pathways in glioblastoma. Expert Opin. Investig. Drugs. 22, 1023–1040 (2013).
- 24 . The EGFRvIII variant in glioblastoma multiforme. J. Clin. Neurosci. 16, 748–754 (2009).
- 25 . Amplification of genes encoding KIT, PDGFRalpha and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme. J. Pathol. 207, 224–231 (2005).
- 26 Somatic mutations of PIK3R1 promote gliomagenesis. PLoS ONE 7, e49466 (2012).
- 27 Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 9, 157–173 (2006).
- 28 . Emerging biomarkers in glioblastoma. Cancers (Basel) 5, 1103–1119 (2013).
- 29 . Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355, 846–847 (1992).
- 30 . Loss of wild-type p53 bestows a growth advantage on primary cortical astrocytes and facilitates their in vitro transformation. Cancer Res. 55, 2746–2751 (1995).
- 31 . Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat. Rev. Clin. Oncol. 10, 14–26 (2013). • Discusses additional potential therapeutic targets in glioma.
- 32 NFKBIA deletion in glioblastomas. N. Engl. J. Med. 364, 627–637 (2011). • New pathway mutation identifed in GBM allows for constitutively active NF-κB.
- 33 . Bevacizumab for the treatment of glioblastoma. Expert Rev. Neurother. 13, 937–949 (2013).
- 34 . Tumor angiogenesis. N. Engl. J. Med. 359, 763; author reply 764 (2008).
- 35 . Angiogenesis in brain tumours. Nat. Rev. Neurosci. 8, 610–622 (2007).
- 36 . Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 67, 1879–1882 (2007).
- 37 . Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers. Lancet Neurol. 9, 717–726 (2010).
- 38 MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005). Landmark paper demonstrating the MGMT gene silencing predicts chemotherapy response.
- 39 . Molecular genetics of oligodendrogliomas: a model for improved clinical management in the field of neurooncology. Neurosurg. Focus. 19, E2 (2005).
- 40 Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 77, 1156–1164 (2011).
- 41 Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial. Acta Neuropathol. 123, 841–852 (2012).
- 42 ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Acta Neuropathol. 126, 443–451 (2013).
- 43 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. 120, 707–718 (2010).
- 44 Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J. Clin. Oncol. 27, 4150–4154 (2009).
- 45 et al. MGMT CpG island is invariably methylated in adult astrocytic and oligodendroglial tumors with IDH1 or IDH2 mutations. Int. J. Cancer 131, 1104–1113 (2012).
- 46 Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. Brain Pathol. 21, 564–574 (2011).
- 47 . Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions. Expert Opin. Investig. Drugs. 21, 1247–1266 (2012).
- 48 . Clinical significance of molecular biomarkers in glioblastoma. Can. J. Neurol. Sci. 37, 625–630 (2010).
- 49 Genetic pathways to glioblastoma: a population-based study. Cancer Res. 64, 6892–6899 (2004).
- 50 . Anti-cancer therapies in high grade gliomas. Curr. Proteomics 10, 246–260 (2013).
- 51 et al. Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to antimitotic drugs. J. Natl Cancer Inst. 105, 1322–1331 (2013).
- 52 Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc. Natl Acad. Sci. USA 110, 5957–5962 (2013).
- 53 Targeted therapy for BRAFV600E malignant astrocytoma. Clin. Cancer Res. 17, 7595–7604 (2011).
- 54 . MicroRNAs in brain tumors : a new diagnostic and therapeutic perspective? Mol. Neurobiol. 44, 223–234 (2011).
- 55 ELTD1, a potential new biomarker for gliomas. Neurosurgery 72, 77–90; discussion 91 (2013).
- 56 A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J. Neurosurg. 95, 190–198 (2001).
- 57 Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 353, 2012–2024 (2005).
- 58 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. 26, 5603–5609 (2008).
- 59 A Phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro Oncol. 12, 95–103 (2010).
- 60 Stratified Phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann. Oncol. 20, 1596–1603 (2009).
- 61 A Phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation. Cancer Chemother. Pharmacol. 65, 353–361 (2010).
- 62 . Receptor tyrosine kinases and targeted cancer therapeutics. Biol. Pharm. Bull. 34, 1774–1780 (2011).
- 63 . Epidermal growth factor receptor: a re-emerging target in glioblastoma. Curr. Opin. Neurol. 25, 774–779 (2012).
- 64 Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities. Nat. Med. 19, 1518–1523 (2013).
- 65 . Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding. Tumour Biol. 34, 1991–2002 (2013).
- 66 . mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia 7, 356–368 (2005).
- 67 . Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov. 5, 671–688 (2006).
- 68 An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009).
- 69 et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480, 387–390 (2011).
- 70 Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma. J. Neurooncol. 107, 133–138 (2012).
- 71 Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J. Clin. Oncol. 27, 2052–2058 (2009).
- 72 Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study. Neuro Oncol. 14, 215–221 (2012).
- 73 . Proteasome inhibition with bortezomib induces cell death in GBM stem-like cells and temozolomide-resistant glioma cell lines, but stimulates GBM stem-like cells’ VEGF production and angiogenesis. J. Neurosurg. 119, 1415–1423 (2013).
- 74 . Valproic acid use during radiation therapy for glioblastoma associated with improved survival. Int. J. Radiat. Oncol. Biol. Phys. 86, 504–509 (2013).
- 75 . Prophylactic antiepileptic drugs in patients with brain tumors. Epilepsy Curr. 5, 182–183 (2005).
- 76 . The use of prophylactic anticonvulsants in patients with brain tumours-a systematic review. Curr. Oncol. 13, 222–229 (2006).
- 77 Phase I study of vorinostat in combination with temozolomide in patients with high-grade gliomas: North American Brain Tumor Consortium Study 04–03. Clin. Cancer Res. 18, 6032–6039 (2012).
- 78 Clinical implications of microRNAs in human glioblastoma. Front. Oncol. 3, 19 (2013).
- 79 Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 57, 4593–4599 (1997).
- 80 Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J. Clin. Oncol. 27, 740–745 (2009).
- 81 Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat. Med. 10, 145–147 (2004).
- 82 . Complete inhibition of angiogenesis and growth of microtumors by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy. Cancer Res. 56, 4032–4039 (1996).
- 83 Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 27, 4733–4740 (2009).
- 84 A randomized Phase II study of bevacizumab versus bevacizumab plus lomustine versus lomustine single agent in recurrent glioblastoma: the Dutch BELOB study. J. Clin. Oncol. 31 (2013).
- 85 Clinicaltrials.gov: US National Library of Medicine 2013. http://clinicaltrials.gov/show/NCTM01290939
- 86 RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). J. Clin. Oncol. 31 (2013).
- 87 OT-03. Phase III trial of bevacizumab added to standard radiotherapy and temozolomide for newly-diagnosed glioblastoma: mature progression-free survival and preliminary overall survival results in AVAglio. Neuro. Oncol. 14(Suppl.), Abstract OT-03 (2012).
- 88 Outcome after bevacizumab clinical trial therapy among recurrent grade III malignant glioma patients. J. Neurooncol. 107, 213–221 (2012).
- 89 Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. J. Clin. Oncol. 29, 2689–2695 (2011).
- 90 . Is there a world beyond bevacizumab in targeting angiogenesis in glioblastoma? Expert Opin. Investig. Drugs. 21, 605–617 (2012).
- 91 Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).
- 92 Blockade of TGF-beta signaling by the TGFbetaR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res. 71, 7155–7167 (2011).
- 93 In vitro and in vivo characterization of a novel Hedgehog signaling antagonist in human glioblastoma cell lines. Int. J. Cancer 131, e33–e44 (2012).
- 94 Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 25, 2524–2533 (2007).
- 95 . Cancer immunoediting in malignant glioma. Neurosurgery 71, 201–222; discussion 222–203 (2012).
- 96 et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 28, 4722–4729 (2010).
- 97 Clinicaltrials.gov. US National Library of Medicine. Phase III Study of Rindopepimut/GM-CSF in Patients With Newly Diagnosed Glioblastoma (ACT IV) (2013) http://clinicaltrials.gov/ct2/show/NCT01480479
- 98 A Phase 2 multicenter trial of autologous heat shock protein-peptide vaccine (HSPPC-96) for recurrent glioblastoma multiforme (GBM) patients shows improved survival compared with a contemporary cohort controlled for age, KPS and extent of resection. AANS (2012).
- 99 . DCVax-Brain and DC vaccines in the treatment of GBM. Expert Opin. Investig. Drugs. 18, 509–519 (2009).
- 100 Clinicaltrials.gov. US National Library of Medicine. Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer. 2013. http://clinicaltrials.gov/show/NCTM01290939