Targeting mitochondrial dependencies in chemo resistant triple negative breast cancer

项目总结 本申请是对特别利益通知(NOSI)的回应，该通知被确认为 不是-CA-22-039。 家长奖的总体目标是确定目标代理人，这些代理人要么单独有效，要么三重有效 阴性乳腺癌(TNBC)，或可克服对常用一线化疗药物的耐药性 它们目前是作为临床标准护理方案的一部分给予的。我们对50TNBC PDX的多组谱分析 用化疗反应数据注释的模型确定线粒体新陈代谢是最重要的 与多西紫杉醇和卡铂单独和联合耐药有关的网络。也许吧 最重要的是，在接受单药多西紫杉醇或卡铂及其组合治疗的42例PDX中，有10例(24%) 对三种治疗中的任何一种都没有表现出部分或完全的反应，因此基本上完全 对这些毒剂有抵抗力。我们对基线PDX组学的分子分析已经确定了氧化磷酸化 (OXPHOS)和线粒体转录和翻译是与两者抗性相关的主要过程 多西紫杉醇和卡铂作为单药以及联合用药。我们在过去也得到了类似的结果 使用AC治疗的研究1。对最近一项未发表的临床研究的分析也观察到了类似的结果。 Trial(Cadence，NCT02547987)。为了克服这种阻力，我们将测试两种小说的有效性 线粒体功能的小分子抑制剂，单独或与标准护理紫杉烷联合使用 或者是铂类化疗药物。我们将在六个广泛表征的PDX中对这些治疗进行评估 我们已经确定的对单一和联合化疗最具耐药性的TNBC模型， 这表明这两种药物靶点的水平更高。LDC204857(德国领先发现中心)是 线粒体RNA聚合酶的抑制剂，从而抑制线粒体的转录。这反过来又扰乱了 电子传递链(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，从而抑制等 超复杂组装和OXPHOS。我们用这些药物在人类TNBC中取得了令人振奋的结果 两种细胞系都已准备好用于临床移植。

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-22-039. 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 Similar results were also observed in an analysis of a recent unpublished clinical trial (CADENCE, NCT02547987).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.