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Development of a Genomic Expression Signature Associated with Chemoresistance

Douglas C Marchion

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National Institutes of Health (NIH)
While triple-negative breast cancer (TNBC) accounts for only 15% of all breast cancers, it is extremely aggressive, both biologically and clinically. T date, no targeted agents have shown effectiveness against TNBC, leaving non-specific drugs as the only chemotherapeutic option. Our preliminary data suggests that the BAD apoptosis and survival pathway and the expression of phospho-BAD may function as a biomarker of chemoresponse as well as a novel target for selective therapy in TNBC. To that end, we have developed a BAD Pathway Gene Expression Signature (BPGES) that associates with the phosphorylation status of BAD protein and cancer cell chemoresistance. The central hypothesis of the proposed work, as supported by our preliminary data, is that the BPGES predicts resistance to chemotherapy and poor survival for patients with breast cancer and associates with the triple-negative phenotype. Furthermore, targeted inhibition of the BAD pathway, and hence the phospho-BAD protein, using pathway-specific agents will increase TNBC sensitivity to chemotherapy via an influence of the phosphorylation status of the BAD protein. The results of this project are expected to reveal novel biomarkers of therapeutic response and aid in the selection of breast cancer patients for future clinical trials combining chemotherapeutic agents with BAD pathway targeted inhibitors.

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