Core-001

核心001

• 批准号: 10710331
• 负责人: Michael T. Lewis
• 金额: $ 20万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10710331
• 关键词: Core; 001

The overall goal of the parent award is to identify targeted agents that are either effective on their own in triple negative breast cancer (TNBC), or that can overcome resistance to commonly used first line chemotherapeutics that are currently given as part of clinical standard of care regimens. Our multi-omic profiling of 50 TNBC PDX models annotated with chemotherapy response data identified mitochondrial metabolism as one of the top networks associated with chemoresistance to both docetaxel and carboplatin, alone and in combination. Perhaps most importantly, of the 42 PDX treated with single agent docetaxel or carboplatin and the combination, 10 (24%) failed to show a partial or complete response to any of the three treatments, and thus are essentially completely resistant to these agents. Our molecular analyses of baseline PDX omics has identified oxidative phosphorylation (oxphos) and mitochondrial transcription and translation as major processes associated with resistance to both docetaxel and carboplatin as single agents, as well as the combination. We obtained similar results in past studies using AC treatment1. Similar results were also observed in an analysis of a recent unpublished clinical trial (CADENCE, NCT02547987). In an attempt to overcome this resistance, we will test the efficacy of two novel small molecule inhibitors of mitochondrial functions, either singly or in combination with standard of care taxane or platinum chemotherapy agents. We will evaluate these treatments in six extensively characterized PDX models of TNBC that we have identified to be most resistant to single and combination chemotherapy treatment, and that express higher levels of the two drug targets. LDC204857 (Lead Discovery Center of Germany) is an inhibitor of mitochondrial RNA polymerase, thus inhibiting mitochondrial transcription. This in turn disrupts production of the electron transport chain (ETC) and oxidative phosphorylation (oxphos). ONC206 (Chimerix Inc) is an agonist of the mitochondrial protease ClpP and inhibitor of dopamine receptor D2, thus inhibiting ETC super-complex assembly and oxphos. We have accrued promising results with these agents in human TNBC cell lines and both are ready for clinical translation.

Parent奖的总体目标是确定目标药物，这些药物要么对三阴性乳腺癌(TNBC)本身有效，要么可以克服目前作为临床标准治疗方案一部分给予的常用一线化疗药物的耐药性。我们对50个带有化疗反应数据的TNBC PDX模型的多组谱分析发现，线粒体代谢是与多西紫杉醇和卡铂单独和联合耐药有关的顶级网络之一。也许最重要的是，在用单药多西紫杉醇或卡铂及其组合治疗的42例PDX中，10例(24%)对这三种治疗中的任何一种都没有表现出部分或完全反应，因此基本上对这些药物完全耐药。我们对基线PDX组学的分子分析发现，氧化磷酸化(OXPHOS)和线粒体转录和翻译是与多西紫杉醇和卡铂作为单一药物以及联合耐药相关的主要过程。我们在过去使用AC治疗的研究中获得了类似的结果1。最近一项未发表的临床试验(Cadence，NCT02547987)的分析也观察到了类似的结果。为了克服这种耐药性，我们将测试两种新型线粒体功能小分子抑制剂的疗效，无论是单独使用还是与标准的紫杉烷或铂类化疗药物联合使用。我们将在六种具有广泛特征的TNBC PDX模型中对这些治疗进行评估，我们已经确定这些模型对单一和联合化疗最具耐药性，并且表达两种药物靶点的水平较高。LDC204857(德国铅发现中心)是一种线粒体RNA聚合酶抑制剂，从而抑制线粒体转录。这反过来又扰乱了电子传输链(ETC)和氧化磷酸化(OXPHOS)的产生。ONC206(Chimerix Inc.)是线粒体蛋白水解酶ClpP的激动剂和多巴胺受体D2的抑制剂，从而抑制ETC超复合体组装和OXPHOS。我们已经在人类TNBC细胞系中使用这些药物取得了令人振奋的结果，这两种药物都已准备好用于临床翻译。