Clinical oncology experience with recently marketed antiangiogenic agents, which inhibit proteins important for tumor angiogenesis, has exposed significant limitations to their efficacy. Bevacizumab, a humanized neutralizing anti-VEGF-A monoclonal antibody, used in combination with cytotoxic chemotherapy for the treatment of metastatic colorectal cancer, represents the best-studied clinical example of targeted antiangiogenic therapy. In this context, bevacizumab provides modestly improved progression-free and overall survival in unselected patient populations via poorly understood mechanisms. Here we review concepts central to the identification and development of biomarkers in order to refine clinical use of bevacizumab in treating colorectal cancer and outline a phenotype-driven strategy for the discovery of high-value candidate biomarkers based on large-scale screening by molecular perturbation.
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