Recent advances in targeted therapy for glioblastoma

Abstract

Glioblastomas are the most common form of brain tumor with a very dismal prognosis. While a standard treatment regimen of surgery followed by chemo/radiotherapy is currently used, this has only marginally improved the survival time of patients with little benefit on tumor recurrence. Although many molecular targets have already been identified and tested in clinical trials, very few are approved for use in clinics. Efforts are ongoing to target newer molecules that could be used for drug development. This review provides up-to-date information on the drugs and their molecular targets, which are currently in different stages of clinical trials. Since multiple signaling pathways are deregulated, it appears that the use of combination drugs along with personalized targeting approach would provide better therapy in the future.

Keywords:

• clinical trials
• epidermal growth factor receptor
• glioblastomas
• glioma stem cells
• platelet-derived growth factor receptor family
• tyrosine kinase inhibitors
• temozolomide
• vascular endothelial growth factor receptor family

Financial & competing interests disclosure

T Srivastava has received financial support from Department of Science and Technology, Indian Council of Medical Research and Department of Biotechnology, Government of India, New Delhi. S Mittal is a recipient of Research Associateship from the Department of Biotechnology, New Delhi. S Pradhan is a recipient of Senior Research Fellowship from Council of Scientific and Industrial Research, Government of India, New Delhi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Malignant glioblastomas are highly heterogeneous, involving various interconnected signaling pathways, silenced or activated, resulting in differential patient responses to a single therapeutic agent. Hence, combination therapies are considered more effective.

• Despite numerous clinical trials, minimal survival benefits are observed. There is a need to identify and develop more number of molecules involved in the most affected pathways as targets at the preclinical levels: those with the maximum number of downstream targets should be prioritized.

• Continuing the interrogation of the molecular mechanisms involved in resistance to EGFR inhibitors. Simultaneously, targeting other molecules involved in pathways converging with EGFR should also be considered.

• Recent trials demonstrated incipient evidence in favor of bevacizumab as an anti-angiogenic therapy. For improving its success, strategies for addressing resistance against bevacizumab will need to include molecular intervention against the invasive capabilities of GBM independent of angiogenesis.

• Considering the heterogeneity of the tumor, stratifying patients based upon their mutation status before therapeutic intervention should be one of the ways to ensure better outcomes in trials.

• Improving drug delivery modalities, combination therapy, immunotherapy, targeting Glioma stem cells and hypoxic microenvironment effectors are some of the promising future approaches.

Notes