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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的该计划的总体目标是开发一种新颖、安全、有效的药物并将其商业化。与蒽环类药物协同治疗，例如阿霉素（DOX，阿霉素），以维持或改善三阴性乳腺癌 (TNBC) 治疗的临床结果以及显着降低蒽环类药物治疗引起的长期心脏毒性相关死亡。乳腺癌是全世界女性最常诊断出的癌症，也是主要原因之一美国女性癌症死亡人数超过 380 万美国女性有乳腺癌病史癌症，包括正在接受治疗的女性和已完成治疗的女性。到了年底，预计美国将有超过 43,000 名女性死于乳腺癌。大约占所有乳房的15% 由于缺乏雌激素受体（ER）、孕激素的表达，癌症被归类为 TNBC 受体（PR）和人表皮生长因子受体2型（HER2）。因此，TNBC 患者不对激素乳腺癌疗法或针对 HER2 的药物有反应。虽然新的治疗选择对于新兴的 TNBC，系统性蒽环类化疗，特别是 DOX，仍然是治疗的标准 TNBC由于其优越的临床疗效。然而，DOX 和其他基于蒽环类药物的疗法会导致剂量依赖性进行性心肌病。乳腺癌幸存者死亡的主要原因是停止治疗数年后经常观察到心力衰竭。已有心脏的乳腺癌患者心脏病或心脏病的危险因素变得特别容易发生迟发性心脏毒性。这开发一种针对 DOX 诱导的心肌病提供保护并具有协同作用的疗法 TNBC 患者的抗肿瘤活性将非常显着。 NovoMedix 开发了安全的口服小分子，具有双重活性特异性 mTORC1 抑制剂和变构 AMPK 激动剂。这些新颖的化合物已证明多项体内研究显示其具有心脏保护和抗癌活性。 NovoMedix 与 Dr. 合作弗吉尼亚联邦大学 (VCU) 的 Salloum 和 Das 博士表明，一种 NM 先导化合物增强 DOX 的抗肿瘤作用，同时减弱 DOX 引起的心脏毒性和左心室毒性 TNBC 小鼠异种移植物中的功能障碍。该项目的具体目标是：1) 扩大规模，2 和 3) 进行额外的动物研究，为临床试验提供信息设计，4) 支持 IND 的研究，包括在大鼠和狗中进行的 7 天探索性非 GLP 研究，以及 5) 预研究 IND 会议。选定的临床候选人将对以下疾病的治疗产生重大影响： TNBC 通过维持或增强优越疗效，同时减轻长期心脏毒性蒽环类药物治疗。