NOVEL DUEL MTOR INHIBITORS/AMPK ACTIVATORS IMPROVE THERAPEUTIC EFFICACY OF DOXORUBICIN AND AMELIORATE ITS ASSOCIATED CARDIOTOXICITY IN MICE
Master of Science
Physiology and Biophysics
Triple-negative breast cancer (TNBC) is a particularly aggressive subset of breast cancer that has a molecular expression profile which lacks the estrogen receptor (ER), progesterone receptor (ER), and human epidermal growth factor receptor type 2 (HER2). No targeted treatment options currently exist for TNBC, unlike other types of breast cancer, and therefore survival rates are far lower for these patients. The current treatment for TNBC is systemic anthracycline chemotherapy, typically doxorubicin (DOX), which has great clinical efficacy in increasing survival. However, DOX induces a dose-dependent progressive cardiomyopathy, which can present years and up to decades after the last treatment. This is a major reason why the leading cause of mortality in breast cancer survivors is heart failure. Minimizing the cumulative dose of DOX by targeting survival signaling pathways in cancer cells as well as providing cardioprotective therapy is of great importance for many cancer patients.
We investigated the cardioprotective effects as well as the anti-tumor capacity of novel duel mTOR inhibitors/AMPK activators, NM-922 and NM-043, on breast cancer cell lines, TNBC tumor xenografts, and their effect on cardiomyocytes and cardiac function. Our results show that cotreatment of NM compounds with DOX resulted in a synergistic increase in breast cancer cell death and reduction in viability as well as protection against DOX-induced cardiomyocyte apoptosis. Furthermore, TNBC tumor xenograft studies showed reduction of tumor size and protection against DOX-induced cardiac dysfunction via preservation of ejection fraction. We propose that combining NM treatment with DOX can be a potential novel treatment for patients with TNBC in hopes of improving the prognosis of this devastating disease.
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Available for download on Wednesday, July 23, 2025