Angiogenic Signaling Pathways and Anti-angiogenic Therapies in Human Cancer

Abstract

Vascular endothelial growth factor (VEGF) is the principal regulator of tumor angiogenesis and is overexpressed in the majority of solid tumors. Therapeutic inhibition of VEGF and its main receptor (VEGFR2) has shown significant clinical efficacy in several human cancers. However, in unselected patient populations, often these agents have not offered sustainable clinical benefit. Some of the challenges with the clinical efficacy of anti-VEGF/VEGFR therapies may be explained by the heterogeneity of human tumor vessels and variation in their sensitivity to VEGF/VEGFR inhibition. However, the process of tumor angiogenesis is far more complex with frequent cross talk between VEGF/VEGFR and other signaling pathways. In addition to anti-angiogenic effects, anti-VEGF/VEGFR agents also cause “normalization” of tumor vessels and “pruning” of normal vessels. In order to achieve significant improvement in clinical efficacy of anti-VEGF/VEGFR therapies in the near future, it will be important to (1) better understand the complex biology of VEGF/VEGFR and non-VEGF/VEGFR signaling pathways in the context of pathologic (aberrant) angiogenesis in human cancer tissues, (2) translate such biologic concepts into a more comprehensive molecular profiling and pathologic disease state characterization, and (3) advance the much needed predictive biomarker science to drive rational patient-tailoring and combinatorial therapeutic strategies in next-generation clinical trials of anti-angiogenic therapies. It will also be critical to identify and address other clinical and scientific challenges, including various primary and acquired mechanisms of resistance to anti-angiogenic therapies.