Sunitinib, sorafenib and mTOR inhibitors in renal cancer

Abstract

Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. Sorafenib and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, VEGFR-3) and platelet-derived growth factor receptor beta (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC.