VEGF: a key therapeutic target for the treatment of cancer-insights into its role and pharmacological inhibition

Abstract

Angiogenesis, the formation of new blood vessels from existing vessels, is required for tumor growth, proliferation, and metastasis. Vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis, activating signaling pathways that in tumors result in immature blood vessels that are disorganized, tortuous, and leaky. Inhibiting VEGF has the potential to reduce vessel abnormalities and inhibit tumor growth. Preclinical and clinical data show that anti-VEGF agents produce a number of effects on the tumor vasculature, including regression of tumor vessels, "normalization" of the surviving vessels, and inhibition of neovascularization. Normalization reduces the characteristically high intratumoral pressure that impairs the delivery of chemotherapy to tumors; this should improve the effectiveness of chemotherapy. These vascular effects are proposed to be dynamic, providing early and continued (late) clinical benefits. Early clinical effects are thought to be reflected by a consistent improvement in response rate with anti-VEGF agents used alone or in combination with standard therapies. In addition, anti-VEGF agents are proven to extend survival and delay disease progression, illustrating continued (late) effects.