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

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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

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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.

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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

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.

Correspondence to Jorg Dietrich.

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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.

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