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In the USA, 38,890 new cases and 12,840 deaths were predicted to occur from renal cell cancer (RCC) in 2006 (1). Although surgery is a potential cure for patients with early stage disease, many patients experience recurrence after surgery or have metastatic disease at the time of diagnosis. Few treatment options have been available for these patients. RCC, a highly vascular disease, is resistant to chemotherapy, with no single agent showing significant antitumor activity (2, 3). Observations of late relapses after nephrectomy, prolonged stabilization of disease in the absence of therapy, and a small number of spontaneous remissions led to trials exploring immunotherapy. Interferon alfa (IFN ?) and interleukin-2 (IL-2) have been widely utilized as treatment for metastatic RCC. However, the majority of patients do not benefit from IFN ? or IL-2, and the few responses seen are not durable, with only about 10% of patients remaining progression free at 3 years (4, 5).
Angiogenesis, the process of new blood vessel formation, is known to play a critical role in the growth of tumors and is believed to be an important target for the development of novel anticancer therapies (6). Recent work in understanding the von Hippel-Lindau (VHL) gene has demonstrated a role for angiogenesis in the pathophysiology of RCC. Clear cell RCC is characterized by its frequent loss of the VHL tumor suppressor gene. VHL normally encodes a protein (p-VHL) that targets hypoxia-inducible factor (HIF) for proteolysis (Figure) (7-12). As a result of VHL inactivation, a defective p-VHL is produced, and HIF is up-regulated (13). Activated HIF then translocates into the nucleus and leads to the transcription of several genes that play a central role in tumorigenesis. These genes include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor-?, and basic fibroblast growth factor (14-20). Angiogenesis is stimulated, in part, by VEGF binding its receptor (VEGFR), and this pathway has been heavily exploited for the therapy of RCC (21). Tumor angiogenesis is also stimulated by growth factors through the phosphatidylinositol-3 kinase PI3K-AKT-mTOR signal transduction pathway (22, 23). Agents targeting this pathway can also be expected to have antitumor activity.
Figure
Consequences of mutation or inactivation of the von Hippel Lindau (VHL) gene. VHL normally encodes a...