Abstract The overall goal of this program is the development and commercialization of a novel, safe, and effective, therapy that synergizes with anthracyclines, such as Doxorubicin (DOX, Adriamycin), to maintain or improve clinical outcome for the treatment of triple negative breast cancer (TNBC) as well as significantly decrease long-term cardiotoxicity-related mortality caused by anthracycline treatment. Breast cancer is the most commonly diagnosed cancer in women worldwide and one of the leading causes of cancer death among women in the U.S. More than 3.8 million women in the U.S. have a history of breast cancer, which includes women currently being treated and women who have finished treatment. By year-end, over 43,000 women in the U.S. are expected to die from breast cancer. Approximately 15% of all breast cancers are categorized as TNBC due to the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2). TNBC patients, therefore, do not respond to hormonal breast cancer therapies or medicines that target HER2. Although new therapeutic options for TNBC are emerging, systemic anthracycline chemotherapy, notably DOX, remains the standard of care for TNBC due to its superior clinical efficacy. However, DOX and other anthracycline-based therapies result in dose-dependent, progressive cardiomyopathy. The leading cause of mortality for breast cancer survivors is heart failure often observed years after cessation of treatment. Breast cancer patients with preexisting heart disease or risk factors for heart disease become especially prone to the delayed cardiotoxicity. The development of a therapy that provides protection against DOX-induced cardiomyopathy and has synergistic anti-tumor activity in TNBC patients would be highly significant. NovoMedix has developed safe, orally-available, small molecules that have dual activity acting as both specific mTORC1 inhibitors and allosteric AMPK agonists. These novel compounds have demonstrated cardioprotective and anti-cancer activity in multiple in vivo studies. NovoMedix, in collaboration with Dr. Salloum and Dr. Das at Virginia Commonwealth University (VCU), has shown that an NM lead compound potentiates the anti-tumor effect of DOX, while attenuating DOX-induced cardiotoxicity and left ventricular dysfunction, in a TNBC mouse xenograft. The specific aims for this project are: 1) scale-up, 2 and 3) additional animal studies to inform clinical trial design, 4) IND-enabling studies including 7- day exploratory, non-GLP studies in rats and dogs, and 5) Pre- IND meeting. The selected clinical candidate will be poised to have a significant impact in the treatment of TNBC by maintaining or enhancing the superior efficacy while mitigating the long-term cardiotoxicity of anthracycline therapy.

Project Narrative The goal of this program is to discover and ultimately commercialize novel, small molecules that synergize with anthracyclines, such as Doxorubicin (Adriamycin), to maintain or improve clinical outcome for the treatment of triple negative breast cancer (TNBC) as well as significantly decrease long-term cardiotoxicity- related mortality from anthracycline treatment, which is the leading cause of death in breast cancer survivors.