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  • Review Article
  • Published:

Antiangiogenic therapies for high-grade glioma

Nature Reviews Neurology volume 5, pages 610–620 (2009)Cite this article

Abstract

High-grade gliomas (HGGs) are vascular tumors that represent attractive targets for antiangiogenic therapies. In this Review, we present the rationale and clinical trial evidence for targeting angiogenesis in HGGs, focusing predominantly on agents that target vascular endothelial growth factor (VEGF) and its receptors. Bevacizumab, a humanized monoclonal antibody against VEGF, was recently approved by the FDA for treatment of recurrent glioblastoma. Bevacizumab prolongs progression-free survival and controls peritumoral edema, but its effects on overall survival remain to be determined. Other inhibitors of VEGF, VEGF receptors and other proangiogenic signaling pathways are being evaluated. Antiangiogenic therapies are well tolerated, although potentially serious adverse events can occasionally occur, and resistance to antiangiogenic therapy inevitably develops. Mechanisms of resistance include upregulation of alternative proangiogenic pathways, and increased perivascular tumor growth. Tumor progression on antiangiogenic agents is a challenging problem for which no effective salvage therapy has been identified. Combining these agents with radiation therapy, cytotoxic chemotherapy, other targeted molecular agents, or anti-invasion therapies could be helpful. The international Response Assessment in Neuro-Oncology Working Group has developed consensus treatment response criteria for HGG that account for the complex effects of antiangiogenic drugs.

Key Points

  • Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), was recently approved by the FDA for treatment of recurrent glioblastoma

  • Various drugs that inhibit VEGF, VEGF receptors or other proangiogenic signaling pathways are being evaluated in clinical trials

  • Bevacizumab and other antiangiogenic therapies are well tolerated by most patients, although potentially serious adverse events, such as hemorrhage or venous thromboembolism, occasionally occur

  • Resistance to antiangiogenic drugs inevitably develops in patients with high-grade glioma

  • Tumor progression on antiangiogenic agents might be delayed by combining these agents with radiation therapy, cytotoxic drugs, other targeted molecular agents, or anti-invasion therapies

  • The optimal manner in which to evaluate response and progression to antiangiogenic therapies has yet to be established

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Figure 1: Angiogenic signaling molecules representing potential therapeutic targets in high-grade glioma.
Figure 2: Mechanisms of resistance to antiangiogenic therapy in high-grade gliomas.
Figure 3: Non-enhancing tumor progression in a patient with high-grade glioma treated with bevacizumab.

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Acknowledgements

The authors gratefully acknowledge the support of the Cairns-Haley and James Canary Brain Tumor Research Funds.

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  1. Division of Neuro-Oncology, Department of Neurology, Department of Medical Oncology, Brigham and Women's Hospital and Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA

    Andrew D. Norden, Jan Drappatz & Patrick Y. Wen

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  1. Andrew D. Norden
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  2. Jan Drappatz
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Correspondence to Patrick Y. Wen.

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Competing interests

A. D. Norden has acted as a consultant for Genentech and has received honoraria from Schering-Plough. P. Y. Wen has received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, Novartis and Schering-Plough. J. Drappetz declares no competing interests.

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Norden, A., Drappatz, J. & Wen, P. Antiangiogenic therapies for high-grade glioma. Nat Rev Neurol 5, 610–620 (2009). https://doi.org/10.1038/nrneurol.2009.159

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