Novel c-Abl-directed Therapies to Alleviate Metastatic Breast Cancer

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DESCRIPTION (provided by applicant): Triple-negative breast cancer (TNBC) is the most aggressive BC subtype and exhibits enhanced rates of metastasis, recurrence, and poor overall survival as compared to their non-TNBC counterparts. Due to the lack of estrogen and progesterone receptors, as well as that of Her2 overexpression, no FDA approved targeted therapies that are effective against TNBCs. As such, this aggressive BC subtype is typically treated with systemic chemotherapies as the standard of care for TNBCs. We previously established c-Abl as a novel suppressor of TNBC tumorigenesis through its inhibition of EMT, invasive, and metastatic phenotypes. Mechanistically, these c-Abl-mediated events transpired through its reactivation of p53 and p21 expression, thereby alleviating TNBC tumor development in mice. Recently, I have associated c-Abl expression with the response of TNBCs to docetaxel, as well as identified the ancient Chinese herb Securinine to mediate anticancer activities against dormant and metastatic TNBCs via a p73- and c-Abl-dependent mechanism. Therefore, I hypothesize that measures capable of activating c-Abl will alleviate TNBC development and metastatic progression. My innovative and translational studies will address the aforementioned hypothesis by determining (i) whether chemotherapeutic activation of c-Abl inhibits TNBC tumorigenicity; (ii) the value of c-Abl to predict for TNBC response to docetaxel; and (iii) the therapeutic effectiveness of Securinine to eradicate TNBCs. Collectively, my application will elucidate major translational advancements for TNBCs through administration of the allosteric c-Abl activator, DPH, together with Securinine to eradicate TNBCs. Finally, c-Abl is will be established as the first predictive biomarker capable of stratifying TNBC patients into docetaxel responders and nonresponders.