Renal cell carcinoma: rationale and development of therapeutic inhibitors of angiogenesis

Inhibition of tumor angiogenesis is a promising therapeutic approach to treat cancer; translation of this concept into clinical practice requires an understanding of the molecular events that are responsible for the development of tumor vasculature. Renal cell carcinoma is characterized by the frequent loss of the von Hippel Lindau tumor suppressor gene, which results in the loss of one of the critical mechanisms for regulating the level of hypoxia inducible factor 1 and leads to the overproduction of vascular endothelial growth factor (VEGF) by the tumor cell. Therapeutic strategies to inhibit the function of these important pathways have been effective in preventing tumor angiogenesis in preclinical models of kidney cancer, and more recently, in the clinical setting. Strategies to treat renal cell carcinoma with agents that are designed to prevent angiogenesis have included interruption of the VEGF signaling pathway, mimics of endogenous angiogenesis inhibitors, prevention of destruction of the basement membrane, and direct inhibition of endothelial cells by a variety of agents with complex, novel, or undetermined mechanisms. Recent clinical studies of bevacizumab, the first anti-VEGF agent to be marketed for the treatment of cancer, have provided proof for the concept that these strategies can lead to tangible benefits for patients who have advanced renal cell carcinoma and likely will be applicable broadly to the treatment of cancer.