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.

抽象的 该计划的总体目的是开发和商业化新颖，安全和有效的， 与蒽环类药物（例如阿霉素（dox，adrimycin））协同的治疗可维持或改善 治疗三重阴性乳腺癌（TNBC）的临床结果，并显着降低 蒽环类药物治疗引起的长期心脏毒性相关死亡率。 乳腺癌是全球女性最常见的癌症，也是主要原因之一 美国妇女中的癌症死亡人数超过380万妇女有乳房的病史 癌症包括目前正在治疗的妇女和完成治疗的妇女。到年底， 预计在美国有超过43,000名妇女死于乳腺癌。大约15％的乳房 由于缺乏雌激素受体（ER），孕酮的表达，癌症被归类为TNBC 受体（PR）和人类表皮生长因子受体2型（HER2）。因此，TNBC患者不 应对针对HER2的激素乳腺癌疗法或药物。虽然新的治疗选择 对于TNBC，全身性蒽环类化疗，尤其是DOX，仍然是护理的标准 TNBC由于其出色的临床功效。但是，DOX和其他基于蒽环类药物的疗法导致 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 停止治疗几年后，心力衰竭经常观察到。乳腺癌患者的心脏 心脏病的疾病或危险因素特别容易受到延迟的心脏毒性。这 开发一种疗法，可保护DOX引起的心肌病并具有协同作用 TNBC患者的抗肿瘤活性将非常重要。 Novomedix已经开发了安全的，口服的小分子，具有双重活性，作为两者兼而有之 特定的MTORC1抑制剂和变构AMPK激动剂。这些新颖的化合物已经证明了 在多个体内研究中，心脏保护和抗癌活性。 Novomedix与博士合作 弗吉尼亚联邦大学（VCU）的Salloum和Das博士表明，NM铅大院 增强DOX的抗肿瘤效应，同时减弱DOX诱导的心脏毒性和左心室 功能障碍，在TNBC小鼠异种移植物中。 该项目的具体目的是：1）扩大规模，2和3）其他动物研究以告知临床试验 设计，4）辅助研究，包括在大鼠和狗中的7天探索性，非GLP研究，以及5） 独立会议。选定的临床候选人将有望在治疗中产生重大影响 TNBC通过保持或增强出色的功效，同时降低长期心脏毒性 蒽环疗法。