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

开发一种新的小分子疗法来治疗耐药性乳腺癌

• 批准号: 9345896
• 负责人: Stan Gee Louie
• 金额: $ 27.99万
• 依托单位: VIOMEDIX, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2019-01-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9345896
• 关键词: Address; Affect; Anthracyclines; Apoptosis; Apoptotic; Autophagocytosis; Biological Markers; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer therapy; Cancer Model; Cancer Patient; Carboplatin; Cause of Death; Cell Death; Cell Survival; Chronic; Clinical; Clinical Research; Colon Carcinoma; Cytotoxic Chemotherapy; Cytotoxic agent; DNA; Development; Diagnosis; Disease; Distant Metastasis; Drug Kinetics; Drug Targeting; Environment; Epidermal Growth Factor Receptor; Estrogen Receptors; Evaluation; Female; Frequencies; GRP78 gene; Glucose; Human; In Vitro; Investigation; Lead; MDA MB 231; MDA-MB-468; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Mediating; Medical; Modality; Modeling; Molecular Chaperones; Normal Cell; Nutrient; Oral; Oxygen; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Preparation; Process; Progesterone Receptors; Property; Proteins; Regimen; Residual Tumors; Resistance; Role; Safety; Schedule; Stress; Therapeutic; Toxic effect; Treatment Efficacy; Woman; Xenograft Model; Xenograft procedure; adduct; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; clinical development; cost effective; design; dosage; drug candidate; effective therapy; endoplasmic reticulum stress; gemcitabine; individual patient; innovation; malignant breast neoplasm; misfolded protein; molecular marker; neoplastic cell; novel; novel strategies; novel therapeutics; outcome forecast; overexpression; pre-clinical; preclinical study; progesterone receptor positive; protein degradation; research clinical testing; response; small molecule; small molecule therapeutics; targeted cancer therapy; taxane; therapy resistant; treatment response; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

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.

项目摘要 /摘要 乳腺癌是癌症女性死亡的第二大原因。 2013年约232,340 诊断出新的侵入性乳腺癌病例，预计估计39,620例 他们的疾病。据估计，八分之一的女性一生中会发展乳腺癌。胸部 根据雌激素受体（ER），孕酮受体的表达，将癌症分为亚型 （PR）和人表皮生长因子受体2（HER2）的扩增。存在或不存在 这些分子标记物已用于估计临床预后，并确定 目前针对这些途径的乳腺癌疗法。尽管有这些治疗性进步，但乳腺癌 无法检测到的ER，PR和HER2（称为三重阴性乳腺癌（TNBC））的患者不能 受益于这些有针对性的治疗。细胞毒性化疗继续是主要治疗选择 对于TNBC患者，比较时的预后较差，总生存率显着降低 对于ER和/或PR阳性的患者。因此，有很大的医疗需要有效 包括TNBC在内的耐药性乳腺癌的长期疗法。 耐药性肿瘤能够在低营养素的敌对肿瘤微环境中生存和繁衍生息 通过通过各种生存机制适应这种有毒环境，例如持续展开，氧气和氧气 蛋白质反应（UPR）或持续性内质网应激（ERS）和自噬。标志的标志 ERS是增强的伴侣蛋白的表达，可促进清除错误折叠的蛋白质，并 结果，它们促进了抗凋亡机制并增强了癌细胞的存活。过表达 这些伴侣蛋白还可以赋予对细胞毒性化疗的耐药性。因此，不是 令人惊讶的是，具有慢性慢性ER水平的肿瘤细胞能够生存甚至繁荣 环境，包括细胞毒性化疗。我们的发现甚至很小 肿瘤细胞中的ER应力水平的增加可能会超过一定阈值，在该阈值中触发凋亡细胞 在肿瘤细胞中特别死亡。 根据我们对这个新颖概念的研究，我们确定了一种铅化合物，该化合物被证明 具有适合于人类评估的功效和安全性。发现这个小分子 活跃在广泛的癌症中，包括肺，脑，乳腺癌和结肠癌 单独活跃并与TNBC中的常规化学疗法结合使用。 该项目将支持我们的铅综合大院迈向临床发展。这将是 单独使用并结合使用时，通过建立最佳剂量和频率来完成 细胞毒性化疗，并确定其药代动力学和药效学。这些努力会 为完成这种有希望的化合物的临床前研究奠定了基础，并将有助于进步 临床研究包括TNBC在内的抗性乳腺癌。