It is just 40 years since Judah Folkman published his classic New England Journal of Medicine paper entitled "Tumor angiogenesis: therapeutic implications" . In that paper he set forth three bold postulates: i. Angiogenesis is essential for tumor growth beyond minimal size. ii. Tumors secrete a "tumor angiogenesis factor" (TAF) that is responsible for inducing angiogenesis. and iii. Anti-angiogenesis is a potential therapeutic strategy for treating cancer. Now, four decades later, after considerable debate and not a little controversy, all three of these postulates are widely accepted. Generally speaking, tumors do need to induce a new vascular supply if they are to grow, though some make do, at least for a time, by coopting the existing host vasculature. Folkman's RNA-like TAF candidate proved to be a blind alley, but the discovery of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF or more simply VEGF-A) and the preparation of antibodies against it provided an opportunity for testing Folkman's hypotheses. VEGFA is widely expressed by nearly all malignant tumors and is generally agreed to be the most important TAF. It acts on vascular endothelial cells (EC) within minutes to induce vascular permeability, and, longer term, reprograms gene expression, leading to EC proliferation and migration in vitro, and, in vivo, generation of new blood vessels. Moreover, a variety of drugs that target VEGFA or its receptors effectively prevent the growth of many mouse tumors and tumor xenografts. Among these drugs are antibodies against VEGFA or its receptors, engineered proteins that mimic VEGF receptors, and small molecule receptor tyrosine kinase (RTK) inhibitors that preferentially target VEGF receptor-2 (VEGFR-2/ flk-1/KDR) with high affinity. Unfortunately, however, the striking benefits of anti-VEGF/VEGFR therapy observed in treating mouse tumors have not been translated to the clinic. All of these drugs have had only modest effects on human cancers and have not lived up to the great expectations that Folkman and many others anticipated. For example, Bevacizumab (Avastin?, Genentech), a humanized antibody against VEGF-A, prolongs the life of patients with advanced colon cancer by, on average, 4-5 months, and then only when combined with triple chemotherapy. In fact, a recent editorial has questioned whether Bevacizumab was "boon or bust" because of its limited effectiveness, serious (though uncommon) side effects, and high cost. Other FDA-approved drugs that bind VEGFA or that target VEGFA receptors, have fared no better.
Sitohy B, Nagy J A, Dvorak H F. Anti-VEGF/VEGFR therapy for cancer: reassessing the target[J]. Cancer research, 2012, 72(8): 1909-1914.