The mechanistic target of Rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cellular growth and metabolism. Two allosteric inhibitors of mTORC1, the rapalogs temsirolimus and everolimus, are FDA approved for renal cell carcinoma (RCC). However, despite the fact that mTORC1 appears to be activated in the majority of RCC, only a subset of patients derives significant clinical benefit from these agents. Currently there are no predictive biomarkers of treatment response to mTORC1 inhibitors in RCC. The recent TCGA analysis of RCC identified multiple genetic alterations that potentially result in constitutive activation of the mTOR pathway (seen in 8-17%, e.g. MTOR). This leads to our first hypothesis, that mutations in genes encoding critical proteins in the PI3K-mTOR pathway will be associated with clinical response to rapalog therapy in RCC. Recently several drugs have been developed that are ATP-competitive mTOR kinase inhibitors. This leads to our second hypothesis, that ATP-competitive mTOR kinase inhibitors will have benefit for patients who progress on rapalog therapy. CRISPR gene editing technology has recently been developed, and enables genome wide screens for enhancers of rapalog effects on cell growth. This leads to our third hypothesis, that a genome-wide CRISPR/Cas9 screen will identify genes that are essential for kidney cancer growth and/or confer synthetic lethality when combined with mTOR inhibition, thereby leading to an improved therapeutic strategy. Hence, our specific aims are: 1A: To identify genetic predictors of response to agents targeting the mTOR pathway in advanced RCC. 1B: To study mechanisms of resistance to mTOR inhibitors occurring in vivo in patients. 2: To conduct an mTOR-kinase inhibitor (MLN0128) trial in metastatic RCC patients who progressed on rapalog therapy, including genetic analysis and cell line development. 3A: To conduct genome-wide CRISPR/Cas9 screens to identify genes essential or conditionally essential upon mTOR inhibition in kidney cancer cells in vitro; to validate and prioritize these genes; and to determine the contribution of hit genes to tumor cell growth in vivo.
The proposed studies will: 1) identify genetically defined subsets of RCC patients that have a sustained clinical response to rapalog therapy, to enable a personalized medicine approach to treatment selection in RCC, and define mechanisms of resistance to rapalogs when they develop; 2) examine the clinical benefit of mTOR kinase inhibitor therapy in RCC; 3) use a novel CRISPR/Cas9 screen to identify synergistic therapeutic approaches to targeting mTOR in RCC.
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