Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end?

Nature Reviews Clinical Oncology volume 10, pages 14–26 (2013)Cite this article

Subjects

Abstract

Glioblastomas are heterogeneous neoplasms that are driven by complex signalling pathways, and are among the most aggressive and challenging cancers to treat. Despite standard treatment with resection, radiation and chemotherapy, the prognosis of patients with glioblastomas remains poor. An increasing understanding of the molecular pathogenesis of glioblastomas has stimulated the development of novel therapies, including the use of molecular-targeted agents. Identification and validation of diagnostic, prognostic and predictive biomarkers has led to the advancement of clinical trial design, and identification of glioblastoma subgroups with a more-favourable prognosis and response to therapy. In this Review, we discuss common molecular alterations relevant to the biology of glioblastomas, targeted, antiangiogenic and immunotherapies that have impacted on the treatment of this disease, and the challenges and pitfalls associated with these therapies. In addition, we emphasize current biomarkers relevant to the management of patients with glioblastoma.

Key Points

  • Large-scale integrative genomic analyses have enhanced our current understanding of glioma biology and identified distinct tumour subtypes

  • Angiogenesis inhibitors and molecular-targeted agents are increasingly incorporated in the management of patients with glioma, although tumour resistance to existing therapies inevitably develops

  • Resistance mechanisms might be overcome by collective inhibition of multiple signalling pathways in selected patient populations

  • Novel immunotherapies in malignant gliomas have had promising results in early clinical trials

  • Several tissue biomarkers, including MGMT promoter methylation, IDH mutations and loss of 1p and 19q have become increasingly important in patient management and clinical trial design

  • Increasing real-time information about molecular and genetic alterations in patients with glioma, combined with the use of novel biomarkers, are likely to shape future therapies towards a more personalized medicine

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Critical signalling pathways altered in malignant gliomas.
Figure 2: Cell signalling pathways in tumour cells and tumour-associated endothelial cells represent important targets for novel treatment strategies.
Figure 3: Pseudo-response and non-enhancing progression with the use of bevacizumab.

Similar content being viewed by others

References

  1. CBTRUS. Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2007 [online], (2011).

  2. Ohgaki, H. & Kleihues, P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J. Neuropathol. Exp. Neurol. 64, 479–489 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Louis, D. N. et al. The World Health Organization classification of tumours of the central nervous system. Acta Neuropathol. 114, 97–109 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Grossman, S. A. et al. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. van den Bent, M. J. et al. A hypermethylated phenotype is a better predictor of survival than MGMT methylation in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. Clin. Cancer Res. 17, 7148–7155 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Cairncross, J. G. et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J. Natl Cancer Inst. 90, 1473–1479 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  11. Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Phillips, H. S. et al. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Huang, H. S. et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J. Biol. Chem. 272, 2927–2935 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Stommel, J. M. et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318, 287–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Snuderl, M. et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20, 810–817 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Szerlip, N. J. 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. USA 109, 3041–3046 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7, 606–619 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer 9, 550–562 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 3, 11–22 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Vousden, K. H. & Lane, D. P. p53 in health and disease. Nat. Rev. Mol. Cell Biol. 8, 275–283 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Sidransky, D. et al. Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355, 846–847 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. Bögler, O., Huang, H. J. & Cavenee, W. K. 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).

    PubMed  Google Scholar 

  24. Reifenberger, G., Liu, L., Ichimura, K., Schmidt, E. E. & Collins, V. P. Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res. 53, 2736–2739 (1993).

    CAS  PubMed  Google Scholar 

  25. Ohgaki, H. & Kleihues, P. Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci. 100, 2235–2241 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Stott, F. J. et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 17, 5001–5014 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Norden, A. D., Drappatz, J. & Wen, P. Y. Antiangiogenic therapies for high-grade glioma. Nat. Rev. Neurol. 5, 610–620 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Gomez-Manzano, C. et al. Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Ann. Neurol. 53, 109–117 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Yoshino, Y. et al. Activation of p38 MAPK and/or JNK contributes to increased levels of VEGF secretion in human malignant glioma cells. Int. J. Oncol. 29, 981–987 (2006).

    CAS  PubMed  Google Scholar 

  30. Kerbel, R. S. Tumor angiogenesis. N. Engl. J. Med. 358, 2039–2049 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jain, R. K. et al. Angiogenesis in brain tumours. Nat. Rev. Neurosci. 8, 610–622 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Shih, Ie-M. & Wang, T. L. Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 67, 1879–1882 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Dietrich, J., Imitola, J. & Kesari, S. Mechanisms of disease: the role of stem cells in the biology and treatment of gliomas. Nat. Clin. Pract. Oncol. 5, 393–404 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Dietrich, J., Diamond, E. L. & Kesari, S. Glioma stem cell signaling: therapeutic opportunities and challenges. Expert Rev. Anticancer Ther. 10, 709–722 (2010).

    Article  PubMed  Google Scholar 

  36. Hovinga, K. E. et al. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 28, 1019–1029 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Vescovi, A. L., Galli, R. & Reynolds, B. A. Brain tumour stem cells. Nat. Rev. Cancer 6, 425–436 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Jansen, M., Yip, S. & Louis, D. N. Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers. Lancet Neurol. 9, 717–726 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Reifenberger, G. & Louis, D. N. Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology. J. Neuropathol. Exp. Neurol. 62, 111–126 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Burger, P. C. et al. Small cell architecture--a histological equivalent of EGFR amplification in glioblastoma multiforme? J. Neuropathol. Exp. Neurol. 60, 1099–1104 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Smith, J. S. et al. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J. Natl Cancer Inst. 93, 1246–1256 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Horbinski, C. et al. Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. Brain Pathol. 21, 564–574 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Camelo-Piragua, S. et al. A sensitive and specific diagnostic panel to distinguish diffuse astrocytoma from astrocytosis: chromosome 7 gain with mutant isocitrate dehydrogenase 1 and p53. J. Neuropathol. Exp. Neurol. 70, 110–115 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Weller, M. et al. Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker? Clin. Cancer Res. 13, 6933–6937 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Hartmann, C. 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. 120, 707–718 (2010).

    Article  PubMed  Google Scholar 

  47. Wick, W. et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 13, 707–715 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. van den Bent, M. J. et al. MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. J. Clin. Oncol. 27, 5881–5886 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Aldape, K., Burger, P. C. & Perry, A. Clinicopathologic aspects of 1p/19q loss and the diagnosis of oligodendroglioma. Arch. Pathol. Lab. Med. 131, 242–251 (2007).

    CAS  PubMed  Google Scholar 

  50. Wick, W. et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J. Clin. Oncol. 27, 5874–5880 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Malmström, A. et al. 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. 13, 916–926 (2012).

    Article  PubMed  CAS  Google Scholar 

  52. Brandes, A. A. et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J. Clin. Oncol. 26, 2192–2197 (2008).

    Article  PubMed  Google Scholar 

  53. Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Haas-Kogan, D. A. et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J. Natl Cancer Inst. 97, 880–887 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Mellinghoff, I. K. et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 353, 2012–2024 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Brown, P. D. et al. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Riemenschneider, M. J., Mueller, W., Betensky, R. A., Mohapatra, G. & Louis, D. N. In situ analysis of integrin and growth factor receptor signaling pathways in human glioblastomas suggests overlapping relationships with focal adhesion kinase activation. Am. J. Pathol. 167, 1379–1387 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chi, A. S. et al. Rapid radiographic and clinical improvement after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition inhibitor. J. Clin. Oncol. 30, e30–e33 (2012).

    Article  PubMed  Google Scholar 

  60. van den Bent, M. J. et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J. Clin. Oncol. 27, 1268–1274 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lassman, A. B. et al. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium Trials 01–03 and 00–01 Clin. Cancer Res. 11, 7841–7850 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Neyns, B. et al. Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann. Oncol. 20, 1596–1603 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Thiessen, B. et al. 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).

    Article  CAS  PubMed  Google Scholar 

  64. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  65. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  66. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  67. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  68. Galanis, E. et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J. Clin. Oncol. 23, 5294–5304 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Kreisl, T. N. et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J. Neurooncol. 92, 99–105 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  71. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  72. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  73. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  74. Wen, P. Y. et al. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99–08. Clin. Cancer Res. 12, 4899–4907 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Reardon, D. A. et al. Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma. Br. J. Cancer 101, 1995–2004 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dresemann, G. et al. Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide. J. Neurooncol. 96, 393–402 (2010).

    Article  CAS  PubMed  Google Scholar 

  77. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  78. Michaud, K. et al. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res. 70, 3228–3238 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  80. Drappatz, J. et al. A phase I trial of LBH589 and bevacizumab for recurrent high-grade glioma (HGG) [abstract]. J. Clin. Oncol. 29 (Suppl.), a2050 (2011).

    Article  Google Scholar 

  81. Galanis, E. et al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J. Clin. Oncol. 27, 2052–2058 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Friday, B. B. et al. 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).

    Article  CAS  PubMed  Google Scholar 

  83. Phuphanich, S. et al. Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma. J. Neurooncol. 100, 95–103 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Weller, M. et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 77, 1156–1164 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  86. Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Liu, G. et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol. Cancer 5, 67 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  91. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  92. Sekulic, A. et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N. Engl. J. Med. 366, 2171–2179 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  94. Cohen, M. H., Shen, Y. L., Keegan, P. & Pazdur, R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14, 1131–1138 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Vredenburgh, J. J. et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol. 25, 4722–4729 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Friedman, H. S. et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 27, 4733–4740 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Kreisl, T. N. et al. 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).

    Article  CAS  PubMed  Google Scholar 

  98. Lai, A. et al. Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J. Clin. Oncol. 29, 142–148 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Sathornsumetee, S. et al. Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol. 12, 1300–1310 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  101. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  102. de Groot, J. F. et al. Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. J. Clin. Oncol. 29, 2689–2695 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Batchelor, T. T. et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J. Clin. Oncol. 28, 2817–2823 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  106. Batchelor, T. et al. The efficacy of cediranib as monotherapy and in combination with lomustine compared to lomustine alone in patients with recurrent glioblastoma: a phase III randomized study. Neuro Oncol. 12 (Suppl. 4), 69–78 (2010).

    Google Scholar 

  107. Gerstner, E. et al. Effects of cediranib, a VEGF signaling inhibitor, in combination with chemoradiation on tumor blood flow and survival in newly diagnosed glioblastoma [abstract]. J. Clin. Oncol. 30 (Suppl.), a2009 (2012).

    Google Scholar 

  108. Wilhelm, S. et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat. Rev. Drug Discov. 5, 835–844 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Hainsworth, J. D. et al. Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first-line treatment of patients with glioblastoma multiforme. Cancer 116, 3663–3669 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Reardon, D. A. et al. Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma. J. Neurooncol. 101, 57–66 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  112. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  113. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  114. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  115. Wen, P. Y. American Society of Clinical Oncology 2010: report of selected studies from the CNS tumors section. Expert Rev. Anticancer Ther. 10, 1367–1369 (2010).

    Article  PubMed  Google Scholar 

  116. Neyns, B. et al. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J. Neurooncol. 103, 491–501 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Drappatz, J. et al. Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma. Int. J. Radiat. Oncol. Biol. Phys. 78, 85–90 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Quant, E. C. et al. Preliminary results from a multicenter, phase II, randomized, noncomparative clinical trial of radiation and temozolomide with or without vandetanib in newly diagnosed glioblastoma (GBM) [abstract]. J. Clin. Oncol. 29 (Suppl.), a2069 (2011).

    Article  Google Scholar 

  119. Kreisl, T. N. et al. A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Neuro Oncol. 12, 181–189 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Avraamides, C. J., Garmy-Susini, B. & Varner, J. A. Integrins in angiogenesis and lymphangiogenesis. Nat. Rev. Cancer 8, 604–617 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Reardon, D. A. et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J. Clin. Oncol. 26, 5610–5617 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Stupp, R. et al. Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 28, 2712–2718 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  124. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  125. Dunn, G. P., Fecci, P. E. & Curry, W. T. Cancer immunoediting in malignant glioma. Neurosurgery 71, 201–222 (2012).

    Article  PubMed  Google Scholar 

  126. Cheever, M. A. et al. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin. Cancer Res. 15, 5323–5337 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Sampson, J. H. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Parsa, A. T. et al. A phase 2 multicenter trial of autologous heat shock protein peptide vaccine (HSPPC-96) for recurrent glioblastoma multiforme (GBM) patients shows improved survival compared to a contemporary cohort controlled for age, KPS and extent of resection [abstract]. J. Neurosurg. 117, A406 (2012).

    Google Scholar 

  129. Wheeler, C. J. & Black, K. L. DCVax-Brain and DC vaccines in the treatment of GBM. Expert Opin. Investig. Drugs 18, 509–519 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Wheeler, C. J. & Black, K. L. Vaccines for glioblastoma and high-grade glioma. Expert Rev. Vaccines 10, 875–886 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  132. Fong, B. et al. Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. PLoS ONE 7, e32614 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Phuphanich, S. et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol. Immunother. http://dx.doi.org/10.1007/s00262-012-1319-0.

  134. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  135. Ardon, H. et al. Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial. Cancer Immunol. Immunother. http://dx.doi.org/10.1007/s00262-012-1261-1.

  136. Simoens, S. Pharmaco-economic aspects of Sipuleucel-T. Hum. Vaccin. Immunother. 8, 506–508 (2012).

    Article  PubMed  Google Scholar 

  137. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Fecci, P. E. et al. Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin. Cancer Res. 13, 2158–2167 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Agarwalla, P., Barnard, Z., Fecci, P., Dranoff, G. & Curry, W. T. Jr. Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors. J. Immunother. 35, 385–389 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Sunayama, J. et al. Crosstalk between the PI3K/mTOR and MEK/ERK pathways involved in the maintenance of self-renewal and tumorigenicity of glioblastoma stem-like cells. Stem Cells 28, 1930–1939 (2010).

    Article  CAS  PubMed  Google Scholar 

  141. Dias-Santagata, D. et al. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol. Med. 2, 146–158 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Cristofanilli, M. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 351, 781–791 (2004).

    Article  CAS  PubMed  Google Scholar 

  143. Weaver, K. D., Grossman, S. A. & Herman, J. G. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma. Cancer Invest. 24, 35–40 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Schiff, D., Wen, P. Y. & van den Bent, M. J. Neurological adverse effects caused by cytotoxic and targeted therapies. Nat. Rev. Clin. Oncol. 6, 596–603 (2009).

    Article  PubMed  Google Scholar 

  146. Macdonald, D. R., Cascino, T. L., Schold, S. C. & Cairncross, J. G. Response criteria for phase II studies of supratentorial malignant glioma. J. Clin. Oncol. 8, 1277–1280 (1990).

    Article  CAS  PubMed  Google Scholar 

  147. Wen, P. Y. et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J. Clin. Oncol. 28, 1963–1972 (2010).

    Article  PubMed  Google Scholar 

  148. Gállego Pérez-Larraya, J. et al. Response assessment in recurrent glioblastoma treated with irinotecan-bevacizumab: comparative analysis of the Macdonald, RECIST, RANO, and RECIST + F criteria. Neuro Oncol. 14, 667–673 (2012).

    Article  PubMed  CAS  Google Scholar 

  149. Norden, A. D. et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70, 779–787 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. Iwamoto, F. M. et al. Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 73, 1200–1206 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Chamberlain, M. C. Radiographic patterns of relapse in glioblastoma. J. Neurooncol. 101, 319–323 (2011).

    Article  PubMed  Google Scholar 

  152. Wick, A. et al. Bevacizumab does not increase the risk of remote relapse in malignant glioma. Ann. Neurol. 69, 586–592 (2011).

    Article  PubMed  Google Scholar 

  153. Sorensen, A. G., Batchelor, T. T., Wen, P. Y., Zhang, W. T. & Jain, R. K. Response criteria for glioma. Nat. Clin. Pract. Oncol. 5, 634–644 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Sorensen, A. G. et al. A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res. 69, 5296–5300 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Gerstner, E. R. & Sorensen, A. G. Diffusion and diffusion tensor imaging in brain cancer. Semin. Radiat. Oncol. 21, 141–146 (2011).

    Article  PubMed  Google Scholar 

  156. Hu, L. S. et al. Reevaluating the imaging definition of tumor progression: perfusion MRI quantifies recurrent glioblastoma tumor fraction, pseudoprogression, and radiation necrosis to predict survival. Neuro Oncol. 14, 919–930 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Ellingson, B. M. et al. Functional diffusion maps (fDMs) evaluated before and after radiochemotherapy predict progression-free and overall survival in newly diagnosed glioblastoma. Neuro Oncol. 14, 333–343 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Andronesi, O. C. et al. Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci. Transl. Med. 4, 116ra4 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Quant, E. C. et al. Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neuro Oncol. 11, 550–555 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Galanis, E. et al. Phase 2 trial design in neuro-oncology revisited: a report from the RANO group. Lancet Oncol. 13, e196–e204 (2012).

    Article  PubMed  Google Scholar 

  161. Wen, P. Y. et al. It is time to include patients with brain tumors in phase I trials in oncology. J. Clin. Oncol. 29, 3211–3213 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Reardon, D. A. et al. Clinical trial end points for high-grade glioma: the evolving landscape. Neuro Oncol. 13, 353–361 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Gilbert, M. R. Recurrent glioblastoma: a fresh look at current therapies and emerging novel approaches. Semin. Oncol. 38 (Suppl. 4), 21–33 (2011).

    Article  Google Scholar 

  164. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Brandes, A. A. et al. Correlations between O6-methylguanine DNA methyltransferase promoter methylation status, 1p and 19q deletions, and response to temozolomide in anaplastic and recurrent oligodendroglioma: a prospective GICNO study. J. Clin. Oncol. 24, 4746–4753 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Cairncross, J. G. et al. Chemotherapy plus radiotherapy (CT-RT) versus RT alone for patients with anaplastic oligodendroglioma: Long-term results of the RTOG 9402 phase III study [abstract]. J. Clin. Oncol. 30 (Suppl.), a2008b (2012).

    Google Scholar 

  167. Bauman, G. S. et al. Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas. Int. J. Radiat. Oncol. Biol. Phys. 48, 825–830 (2000).

    Article  CAS  PubMed  Google Scholar 

  168. van den Bent, M. J. et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J. Clin. Oncol. 24, 2715–2722 (2006).

    Article  CAS  PubMed  Google Scholar 

  169. Rivera, A. L. et al. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol. 12, 116–121 (2010).

    Article  CAS  PubMed  Google Scholar 

  170. Esteller, M. et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N. Engl. J. Med. 343, 1350–1354 (2000).

    Article  CAS  PubMed  Google Scholar 

  171. Hegi, M. E. et al. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J. Clin. Oncol. 26, 4189–4199 (2008).

    Article  CAS  PubMed  Google Scholar 

  172. Gerstner, E. R. et al. Mgmt methylation is a prognostic biomarker in elderly patients with newly diagnosed glioblastoma. Neurology 73, 1509–1510 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Franceschi, E. et al. Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Br. J. Cancer 96, 1047–1051 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the support of the National Institute of Health (K24-CA125440, R01-CA129371, R01-CA117079-02, R01-CA57683), the American Academy of Neurology Foundation (J. Dietrich), the Stephen E. & Catherine Pappas Cancer Research Foundation (J. Dietrich), and gifts from the Montesi Family Research Fund and the Simches Fund for Brain Tumor Research. J. Dietrich is a fellow of the Clinical Investigator Training Program at Beth Israel Deaconess Medical Center, Harvard Medical School.

Author information

Authors and Affiliations

  1. Stephen E. and Catherine Pappas Center for Neuro-Oncology, Boston, 02114, MA, USA

    Shota Tanaka, Tracy T. Batchelor & Jorg Dietrich

  2. Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Yawkey 9E, Boston, 02114, MA, USA

    David N. Louis

  3. Department of Neurosurgery, Massachusetts General Hospital, 55 Fruit Street, Yawkey 9E, Boston, 02114, MA, USA

    William T. Curry

Authors
  1. Shota Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David N. Louis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William T. Curry
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tracy T. Batchelor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jorg Dietrich
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S. Tanaka and J. Dietrich researched data for the article. All authors made a substantial contribution to the discussion of the content and to writing the manuscript. S. Tanaka, T. T. Batchelor, D. Louis and J. Dietrich edited and reviewed the article before submission.

Corresponding author

Correspondence to Jorg Dietrich.

Ethics declarations

Competing interests

T. T. Batchelor acts as a consultant for Advance Medical, Champions Biotechnology, Kirin Pharmaceuticals, Merck & Co., Roche Pharmaceuticals and Spectrum Pharmaceuticals. In addition, he receives research support from AstraZeneca, Pfizer and Millennium. The other authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanaka, S., Louis, D., Curry, W. et al. Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end?. Nat Rev Clin Oncol 10, 14–26 (2013). https://doi.org/10.1038/nrclinonc.2012.204

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2012.204

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer