Novel small molecules for protection against doxorubicin cardiotoxicity in TNBC

摘要 该项目的总体目标是开发一种新颖、安全和有效的 与多柔比星(DOX、阿霉素)等蒽环类药物协同作用以维持或改善的治疗方法 三阴性乳腺癌(TNBC)的临床疗效及显著下降 由蒽环类药物治疗导致的长期心脏毒性相关死亡率。 乳腺癌是全世界女性中最常见的癌症，也是导致乳腺癌的主要原因之一。 超过380万美国女性有乳房史 癌症，包括目前正在接受治疗的女性和已经完成治疗的女性。到年底， 预计美国将有超过4.3万名女性死于乳腺癌。约占所有乳房的15% 由于缺乏雌激素受体(ER)和孕激素的表达，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患者不会 对荷尔蒙乳腺癌疗法或针对HER2的药物有反应。尽管新的治疗方案 对于TNBC来说，全身蒽环类化疗，特别是DOX，仍然是治疗的标准 TNBC因其优越的临床疗效。然而，DOX和其他基于蒽环类药物的治疗会导致 剂量依赖的进行性心肌病。乳腺癌幸存者死亡的主要原因是 心力衰竭通常在停止治疗数年后观察到。既往心脏存在的乳腺癌患者 疾病或心脏病的危险因素特别容易出现延迟性心脏毒性。这个 开发一种对DOX诱导的心肌病提供保护并具有协同作用的治疗方法 TNBC患者的抗肿瘤活性将具有非常重要的意义。 NovoMedex已经开发出安全的、口服可用的小分子，这些小分子具有双重活性，既可以充当 特异性mTORC1抑制剂和变构AMPK激动剂。这些新化合物已经证明 多项体内研究中的心脏保护和抗癌活性。NovoMedex，与Dr. Salloum和弗吉尼亚联邦大学(VCU)的Das博士已经证明了一种NM先导化合物 增强DOX的抗肿瘤作用，同时减轻DOX的心脏毒性和左心室 在TNBC小鼠异种移植中，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)启用IND的研究，包括为期7天的大鼠和狗的探索性、非GLP研究，以及5)预 IND会议。被选中的临床候选人将在治疗上产生重大影响 TNBC通过维持或增强优越的疗效，同时减轻TBC的长期心脏毒性 蒽环类药物疗法。

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.