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. NovoMedixâs 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 NovoMedixâs 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.
Public Health Relevance Statement: Project Narrative The goal of this program is to discover and ultimately commercialize novel, small molecules for co- adminstration with anthracyclines (e.g. Doxorubicin (DOX), Adriamycin) to improve clinical outcome for the treatment of triple negative breast cancer (TNBC) by significantly decreasing long-term cardiotoxicity-related mortality, a leading cause of death in breast cancer survivors. These novel orally available small molecules 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. The selected clinical candidate will be poised to have significant impact in the treatment of TNBC by maintaining or enhancing the efficacy of anthracycline therapy while mitigating long-term cardiotoxicity.
NIH Spending Category: Biotechnology; Breast Cancer; Cancer; Cardiovascular; Heart Disease; Minority Health; Women's Health
Project Terms: Acute; Adriamycin PFS; Adult; advanced disease; Agonist; Animal Model; Anthracyclines; anti-cancer; anticancer activity; antitumor effect; Biological; Breast Cancer cell line; Breast Cancer Patient; Breast Cancer survivor; Breast Cancer Treatment; cancer diagnosis; Cancer Etiology; Cancer Patient; cancer therapy; Cardiac Myocytes; Cardiomyopathies; cardioprotection; Cardiotoxicity; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; chemotherapy; Clinical; clinical candidate; clinical efficacy; coronary fibrosis; Diagnosis; Disease; Dose; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug resistance; Epidermal Growth Factor Receptor; Estrogen Receptors; Ethnic Origin; Exhibits; experimental study; Future; Genetic; Goals; Heart; Heart Diseases; Human; Immune checkpoint inhibitor; Immunooncology; Immunotherapy; improved; In Vitro; in vitro testing; in vivo; inhibitor/antagonist; Lead; malignant breast neoplasm; Malignant Neoplasms; Metformin; Modality; mortality; Mus; Neoplasm Metastasis; novel; Oral; Pharmaceutical Preparations; Pharmacology; Phase; preclinical safety; prevent; Prevention; Progesterone Receptors; programs; Property; Pulmonary Fibrosis; Race; Recurrence; Regimen; response; Risk; Safety; scale up; small molecule; standard of care; Survival Rate; targeted treatment; Testing; Therapeutic; TimeLine; Toxic effect; Toxicology; Treatment outcome; triple-negative invasive breast carcinoma; tumor; United States; Ventricular; Withholding Treatment; Woman; Xenograft Model; Xenograft proced
