Phase I Amount
$1,062,913
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.
Public Health Relevance Statement: 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.
Project Terms: Animals; inhibitor; Anthracycline; malignant breast neoplasm; Breast Cancer; malignant breast tumor; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cardiovascular Diseases; cardiovascular disorder; Cause of Death; Crystallization; Cessation of life; Death; Diagnosis; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Doxorubicin; 14-Hydroxydaunomycin; Adriamycine; Doxorubicina; Hydroxyl Daunorubicin; Hydroxyldaunorubicin; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Fibrosis; Future; Goals; Heart; Heart Diseases; Cardiac Diseases; Cardiac Disorders; heart disorder; Heart failure; cardiac failure; Recording of previous events; History; Human; Modern Man; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Inflammation; Investments; Lead; Pb element; heavy metal Pb; heavy metal lead; Medicine; mortality; Mus; Mice; Mice Mammals; Murine; Metastasis; Metastasize; Metastatic Lesion; Metastatic Mass; Metastatic Neoplasm; Metastatic Tumor; Secondary Neoplasm; Secondary Tumor; cancer metastasis; tumor cell metastasis; Neoplasm Metastasis; Patents; Legal patent; Pharmacokinetics; Drug Kinetics; Domestic Rabbit; Rabbits; Rabbits Mammals; Oryctolagus cuniculus; Common Rat Strains; Rat; Rats Mammals; Rattus; EGF Receptor; EGFR; ERBB Protein; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epidermal Growth Factor-Urogastrone Receptors; HER1; TGF-alpha Receptor; Transforming Growth Factor alpha Receptor; Urogastrone Receptor; c-erbB-1; c-erbB-1 Protein; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; proto-oncogene protein c-erbB-1; Epidermal Growth Factor Receptor; Estrogen Receptors; Progestin Receptors; Progesterone Receptors; Recurrent; Recurrence; Risk; Risk Factors; Safety; Savings; salt; Sodium Chloride; Survival Rate; Toxicology; Universities; Virginia; Woman; Interleukin-11; IL-11; IL11; Treatment outcome; base; improved; Clinical; Phase; Left Ventricular Dysfunction; Funding; Agonist; Collaborations; Adriablastin; Adriablastine; Adriacin; Adriamycin RDS; Adriblastin; Adriblastina; Adriblastine; Adrimedac; DOXO-CELL; Doxolem; Doxorubin; Farmiblastina; Liposomal Adriamycin; Rubex; adriamycin; Adriamycin PFS; Attenuated; Malignant Cell; cancer cell; Life; programs; Oral; Clinic; Hormonal; Heterograft; Heterologous Transplantation; Xenograft; Xenotransplantation; xeno-transplant; xeno-transplantation; Xenograft procedure; meetings; Cell Growth in Number; Cell Multiplication; Cellular Proliferation; Cell Proliferation; Toxicities; Toxic effect; advanced illness; advanced disease; novel; Modality; cardiovascular risk; cardiovascular risk factor; Modeling; Property; cessation of treatment; treatment cessation; Withholding Treatment; Cardiac Toxicity; Cardiotoxic; Cardiotoxicity; Myocardial Diseases; Myocardial Disorder; Myocardiopathies; myocardium disease; myocardium disorder; Cardiomyopathies; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; cancer diagnosis; heart disease risk; cardiac disease risk; cardiac disorder risk; heart disorder risk; preventing; prevent; small molecule; FK506 Binding Protein 12-Rapamycin Associated Protein 1; FKBP12 Rapamycin Complex Associated Protein 1; FRAP1; FRAP2; Mechanistic Target of Rapamycin; RAFT1; mTOR; mammalian target of rapamycin; FRAP1 gene; Dose; Breast Cancer Treatment; in vivo; Cancer Etiology; Cancer Cause; Cancer Patient; Clinical Trials Design; Development; developmental; triple-negative invasive breast carcinoma; TNBC; triple-negative breast cancer; clinical efficacy; scale up; anticancer activity; anti-cancer activity; migration; chemotherapy; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; mouse model; murine model; commercialization; tumor; standard of care; effective therapy; effective treatment; Regimen; targeted treatment; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; Breast Cancer Patient; Breast Tumor Patient; Breast Cancer survivor; Breast Cancer therapy; antitumor effect; anti-tumor effect; clinical candidate; efficacy study; Inflammasome; cardioprotection; cardioprotectant; cardioprotective; heart damage; cardiac damage
