Integration of Genomic, Biologic, and Chemical Approaches to Target p53 Loss and Gain-of-Function in Triple Negative Breast Cancer
Technical Report,01 Sep 2014,31 Aug 2015
VANDERBILT UNIV NASHVILLE TN NASHVILLE United States
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This is the second annual progress report for DoD Award W81XWH-13-1-0287 BC123219, investigating biochemical states resulting from alterations in the p53 signaling pathway in triple negative breast cancer TNBC. Development of therapies for TNBC is a clinical and scientific challenge due to the heterogeneity of the disease and the lack of recurrent, drug-targetable molecular alterations. Our research focuses on the p53 tumor suppressor pathway, which is altered in the majority of TNBC cases and produces two adaptive states loss of function LOF of wild-type p53 through mutation, gene silencing, or amplification of negative p53 regulators, and gain of function GOF displayed by some hotspot p53 mutant proteins that accumulate to high levels within the cell and drive oncogenic phenotypes including growth, migration, and drug resistance. We hypothesize that targeting these adaptive biochemical states will provide candidate therapeutic targets for a large fraction of TNBC, a cancer for which there are no molecular targets to date. We are pursuing two specific aims 1 to identify which signaling pathways, in either adaptive state, are required for TNBC cell viability, and 2 to test validated targets for druggability by fragment-based screening and develop small molecular inhibitors against targets that are both valid and druggable.