Research Project
9852364
Project Summary The overall goal of this program is to discover and develop a first-in-class small molecule that provides cardioprotective and beneficial anti-tumor effects with standard-of-care chemotherapies for the treatment of triple negative breast cancer (TNBC). One in 8 women in the United States will develop invasive breast cancer during her lifetime. Breast cancer is the most commonly diagnosed cancer in women worldwide and one of the leading causes of cancer death among women of all races and ethnicities in the U.S. Over 266,000 new cases of breast cancer are projected to be diagnosed in the U.S. in 2018, and over 41,000 people in the U.S. are estimated to die this year from this devastating disease. Approximately 15% of all breast cancers are categorized as triple-negative breast cancer due to the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2). Unlike other forms of breast cancer, no targeted therapy exists for TNBC. Systemic chemotherapy is usually the first line of treatment; however, currently available regimens often fail to control advanced TNBC. Anthracyclines like doxorubicin (DOX, Adriamycin) are a leading modality for treating breast cancer patients due to their superior clinical efficacy. Unfortunately, treatment with DOX is associated with a dose-dependent delayed and progressive cardiomyopathy often observed years after cessation of treatment. The leading cause of death in breast cancer survivors is cardiovascular disease, which is often caused by the very treatments that once saved their lives. Additionally, many cancer patients have pre-existing heart disease that could be exacerbated by chemotherapy. NovoMedix has discovered novel small-molecule allosteric AMPK agonists that are also strong mTORC1 inhibitors; these are concerted biological properties not found in existing therapeutics and thus represent a new promising treatment that will provide protection against DOX-induced cardiomyopathy while maintaining or enhancing anti-tumor activity in TNBC. NovoMedix?s lead compounds have demonstrated anti-cancer (alone and in combination with DOX), anti-fibrotic, and cardioprotective (against DOX-induced cardiotoxicity) properties with an excellent preclinical safety profile. Consistent with this, these novel compounds have exhibited remarkable safety and efficacy when administered orally in independent animal models of TNBC and pulmonary and cardiac fibrosis. The Phase I goal is demonstration of proof of concept that NovoMedix?s lead compounds reduce DOX- induced cardiotoxicity in TNBC while maintaining or enhancing efficacy. The specific aims for this Phase I proposal are: 1) i confirm safety and PK properties in combination with DOX; 2) mechanism of cardioprotection studies; and 3) prevention of DOX-induced cardiotoxicity in a xenograft model of TNBC.
