In the last few years, enhanced understanding of the biology of clear cell renal cell carcinoma has led to the development of molecular signaling inhibitors, which, with their superior anti-tumor activity demonstrated in randomized clinical trials, have led to a paradigm shift in the treatment of advanced renal cell carcinoma from cytokine-based therapy to signaling-inhibitor therapy. Relevant therapeutic signaling pathways that have emerged are VEGF receptor and mammalian target of rapamycin pathways, and signaling inhibitors sunitinib, sorafenib, temsiroiimus and, most recently, everolimus are approved by the FDA for treatment of advanced renal cell carcinoma in the USA. Newer agents with promising anti-tumor activity are in continued development, as are efforts to uncover additional therapeutic targets. Currently, the optimal use of available agents, such as sequence and combination strategies, as well as their role in the adjuvant and neoadjuvant setting, remain unclear and investigative efforts are underway.
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