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Drug Insight: antiangiogenic therapies for gastrointestinal cancers—focus on monoclonal antibodies

A Corrigendum to this article was published on 12 August 2008

Abstract

Tumor angiogenesis is strongly induced by vascular endothelial growth factor (VEGF), which is overexpressed in most human gastrointestinal cancers. VEGF overexpression is known to be associated with poor prognosis and survival in patients with various solid tumors. The humanized monoclonal anti-VEGF antibody bevacizumab (Avastin®, Genentech Inc., South San Francisco, CA) is a prototypic antiangiogenic compound, and has proven therapeutic benefit combined with conventional chemotherapy—namely, significantly improved progression-free survival in patients with metastatic colorectal cancer. Bevacizumab is the only anti-VEGF antibody that has been approved by the FDA and the European Medicines Agency for the treatment of metastatic colorectal cancer. Several ongoing clinical studies are evaluating the potential of bevacizumab therapy for other gastrointestinal cancers, in combination with chemotherapy, other targeted therapies and/or radiation. Soluble chimeric receptors, tyrosine kinase inhibitors, and monoclonal antibodies against VEGF and molecular targets in the integrin and Delta-like protein 4–Notch pathways are being developed. As tumors acquire resistance to anti-VEGF therapy, further development of antiangiogenic and vascular targets and therapy is warranted.

Key Points

  • Vascular endothelial growth factor (VEGF) and VEGF receptors are overexpressed in most human gastrointestinal cancers and this overexpression is associated with poor prognosis

  • Monoclonal antibodies, tyrosine kinase inhibitors and soluble chimeric receptors that bind various targets in the VEGF pathway (including VEGF, the external domain of the VEGF receptor, and the intracellular tyrosine-kinase domains of VEGF receptors) are currently being studied as potential antiangiogenic treatments

  • Monoclonal antibodies and multitargeted tyrosine-kinase inhibitors that are specific for other pathways and critical for targeting angiogenesis and tumor vascularization are currently under investigation in preclinical and clinical trials

  • When combined with cytotoxic agents, anti-VEGF therapy with bevacizumab can increase overall survival and/or progression-free survival in patients with colorectal cancer

  • Anti-VEGF therapy with bevacizumab is being studied in various other gastrointestinal cancers such as hepatocellular carcinoma, gastric cancer and pancreatic cancer

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Figure 1: Mechanistic view of antiangiogenic therapy.
Figure 2: Roles of VEGF and DLL4 in the regulation of tumor angiogenesis.

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Correspondence to Wolff Schmiegel.

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Anke Reinacher-Schick has received grant and/or research support from Amgen, Roche and Sanofi-Aventis. Michael Pohl has received grant and/or research support from Merck, Merck Sharp and Dohme, and Roche, and is a stockholder and/or director of Bayer and Novartis. Wolff Schmiegel has received travel grants from Astra-Zeneca, Roche, and Sanofi-Aventis.

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Reinacher-Schick, A., Pohl, M. & Schmiegel, W. Drug Insight: antiangiogenic therapies for gastrointestinal cancers—focus on monoclonal antibodies. Nat Rev Gastroenterol Hepatol 5, 250–267 (2008). https://doi.org/10.1038/ncpgasthep1097

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