Novel small molecules for protection against doxorubicin cardiotoxicity in TNBC

用于保护 TNBC 免受阿霉素心脏毒性的新型小分子

• 批准号: 10617848
• 负责人: Anindita Das
• 金额: $ 93.06万
• 依托单位: NOVOMEDIX, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10617848
• 关键词: Adriamycin PFS; Agonist; Animals; Anthracycline; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer survivor; Breast Cancer therapy; Cancer Etiology; Cancer Patient; Canis familiaris; Cardiomyopathies; Cardiotoxicity; Cardiovascular Diseases; Categories; Cause of Death; Cell Proliferation; Cessation of life; Clinic; Clinical; Clinical Trials Design; Collaborations; Development; Diagnosis; Dose; Doxorubicin; Drug Kinetics; Drug resistance; Epidermal Growth Factor Receptor; Estrogen Receptors; Fibrosis; Funding; Future; Goals; Heart; Heart Diseases; Heart failure; Hormonal; Human; Immunotherapy; In Vitro; Inflammasome; Inflammation; Interleukin-11; Invaded; Investments; Lead; Left Ventricular Dysfunction; Legal patent; Life; Malignant Neoplasms; Medicine; Modality; Modeling; Mus; Neoplasm Metastasis; Oral; Oryctolagus cuniculus; Phase; Phase I Clinical Trials; Progesterone Receptors; Property; Rattus; Recording of previous events; Recurrence; Regimen; Risk; Risk Factors; Safety; Sodium Chloride; Survival Rate; Toxic effect; Toxicology; Treatment Efficacy; Treatment outcome; Universities; Virginia; Withholding Treatment; Woman; Xenograft procedure; advanced disease; anticancer activity; antitumor effect; cancer cell; cancer diagnosis; cancer therapy; cardioprotection; cardiovascular risk factor; chemotherapy; clinical candidate; clinical efficacy; commercialization; efficacy evaluation; efficacy study; heart damage; heart disease risk; improved; in vivo; inhibitor; mTOR inhibition; malignant breast neoplasm; migration; mortality; mouse model; novel; novel therapeutics; pre-Investigational New Drug meeting; prevent; programs; scale up; small molecule; standard of care; synergism; targeted treatment; triple-negative invasive breast carcinoma; tumor

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.

摘要