Development of a new small molecule therapeutic for the treatment of resistant breast cancer

项目摘要/摘要 乳腺癌是女性癌症患者的第二大死因。2013年约有232,340人 诊断出新的浸润性乳腺癌病例，预计将有39620人死亡 对他们的疾病。据估计，每八名女性中就有一人会在一生中患上乳腺癌。乳房 根据雌激素受体(ER)、孕激素受体(PR)的表达将癌症分为不同亚型 (PR)和人表皮生长因子受体2(HER2)的扩增。存在或不存在 这些分子标志物已被用于评估临床预后和确定治疗反应。 目前针对这些途径的乳腺癌治疗方法。尽管有这些治疗上的进步，乳腺癌 ER、PR和HER2检测不到的患者，称为三阴性乳腺癌(TNBC)，不能 从这些有针对性的治疗中受益。细胞毒性化疗仍然是主要的治疗选择 对于TNBC患者，通常预后较差，总体存活率显著低于 ER和/或PR阳性的患者。因此，有一个重大的未得到满足的医学需求，即开发有效的 耐药乳腺癌的长期治疗，包括TNBC。 耐药肿瘤能够在低营养的恶性肿瘤微环境中存活和生长。 和氧气通过各种生存机制来适应这种有毒的环境，如持续展开 蛋白质反应(UPR)或持续内质网应激(ERS)，以及自噬。的标志 ERS是伴侣蛋白的增强表达，有助于错误折叠的蛋白的清除，以及 因此，它们促进了抗凋亡机制，提高了癌细胞的存活率。过度表达…… 这些伴侣蛋白还可以对细胞毒性化疗产生抵抗力。因此，它不是 令人惊讶的是，患有慢性低水平ERS的肿瘤细胞能够在恶劣的环境中存活甚至茁壮成长 环境，包括细胞毒性化疗。这个项目得到了我们的发现的支持，即使是一个很小的 肿瘤细胞中内质网应激水平的增加可以超过一定的阈值，从而触发细胞凋亡 尤其是在肿瘤细胞中死亡。 基于我们对这一新概念的研究，我们发现了一种先导化合物，它被证明是 具有适合人类评估的有效性和安全性特征。这种小分子被发现 在包括肺癌、脑癌、乳腺癌和结肠癌在内的多种癌症中都很活跃，而且被证明是 单用或联合常规化疗治疗TNBCs 该项目将支持我们的先导化合物在临床开发方面的进展。这将是 通过确定单独和联合使用时的最佳剂量和频率来实现 细胞毒性化疗，并测定其药代动力学和药效学。这些努力将 为完成这种有希望的化合物的临床前研究奠定基础，并将有助于推动这一进程 用于包括TNBC在内的耐药乳腺癌的临床研究。

PROJECT SUMMARY / ABSTRACT Breast cancer is the second leading cause of death in females with cancer. In 2013 approximately 232,340 new cases of invasive breast cancer were diagnosed, where an estimate of 39,620 was expected to succumb to their disease. It is estimated that one in eight women will develop breast cancer in their lifetime. Breast cancer is classified into subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR) and amplification of human epidermal growth factor receptor 2 (HER2). The presence or absence of these molecular markers has been used to estimate clinical prognosis and to determine treatment response to current breast cancer therapies targeting these pathways. Despite these therapeutic advances, breast cancer patients that have undetectable ER, PR and HER2, known as triple negative breast cancer (TNBC) cannot benefit from these targeted treatments. Cytotoxic chemotherapy continues to be the primary treatment option for TNBC patients, which typically have poor prognosis and significantly lower overall survival when compared to patients that are ER and/or PR positive. Thus, there is a major unmet medical need to develop effective long-term therapies for resistant breast cancers, including TNBC. Resistant tumors are able to survive and thrive in the hostile tumor microenvironment with low nutrients and oxygen by adapting to such toxic milieu through various survival mechanisms, such as sustained unfolded protein response (UPR) or persistent endoplasmic reticulum stress (ERS), and autophagy. The hallmark of ERS is the enhanced expression of chaperone proteins that facilitate the clearance of misfolded proteins, and as a result they promote anti-apoptotic mechanisms and enhance cancer cell survival. The overexpression of these chaperone proteins can also confer resistance towards cytotoxic chemotherapy. Therefore, it is not surprising that tumor cells with chronic low level of ERS are able to survive and even thrive in inhospitable environments, including cytotoxic chemotherapy. This project is supported by our findings that even a small increase in the ER stress levels in tumor cells can surpass a certain threshold where it triggers apoptotic cell death specifically in tumor cells. Based on our investigations of this novel concept, we identified a lead compound, which was shown to have efficacy and safety profile suitable to advance for human evaluation. This small molecule was found to be active in a wide range of cancers including, lung, brain, breast, and colon cancers, and was shown to be active alone and in combination with conventional chemotherapy in TNBCs. This project will support the advancement of our lead compound towards clinical development. This will be accomplished by establishing the optimal dosage and frequency when used alone and in combination with cytotoxic chemotherapy, and by determining its pharmacokinetics and pharmacodynamics. These efforts will set the stage for completing the preclinical studies of this promising compound, and will help advance it towards clinical studies for resistant breast cancers, including TNBC.