The mechanistic Target of Rapamycin (mTOR) inhibitors (temsirolimus or everolimus) are standard options in advanced renal cell cancer (RCC). Despite the obvious clinical benefit compared to the control arms from the phase 3 registration trials (IFN-� or placebo), these drugs are expensive, can carry significant toxicitiesand most important, responses are usually short-lived. At present, there are no clinically useful predictive biomarkers of response or resistance to targeted therapy in metastatic RCC. Several lines of evidence suggest that treatment outcome is likely to be determined by particular genetic alterations and signaling pathways activated in individual tumors. In a preliminary experiment on 11 tumors from RCC patients who responded to temsirolimus, we noted that 6 of the 11 (55%) responders had a variant in 1 or more mTOR pathway genes. This compares to a background of ~15-20% mTOR pathway mutations in an unselected RCC population. Our first aim is to identify genetic predictors of response to agents targeting the mTOR pathway in RCC using targeted sequencing of all RCC and mTOR pathway genes. Our second aim is to identify acquired mutations that develop in tumors that initially respond to mTOR inhibitors and then progress, using whole exome sequencing of matched pre and post-progression samples. Our long term objective is to perform a definitive test of the hypothesis that mTOR pathway mutations are associated with clinical benefit to rapalogues in RCC. In term of public health significance, our work should allow us to identify those patients with the highest chance of benefit to mTOR inhibitors, and enable an understanding of mechanisms of resistance to these therapies; thereby we will improve both the survival and quality of life of patients with advanced RCC by developing an individualized therapeutic approach. Our project is likely to translate into clinical application within a short period of time and be of major relevance to the field of kidneycancer, a disease that results in more than 13,000 US deaths annually.
