Targeting mitochondrial dependencies in chemo resistant triple negative breast cancer

针对化疗耐药三阴性乳腺癌的线粒体依赖性

• 批准号: 10581266
• 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: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581266
• 关键词: Agonist; Apoptosis; Award; Biological; Biological Assay; Body Weight; Breast Cancer Model; Breast Cancer cell line; Cancer Burden; Carboplatin; Cells; Cessation of life; Chemoresistance; Citric Acid Cycle; Clinical; Clinical Trials; Collection; Combination Drug Therapy; Complex; DNA-Directed RNA Polymerase; DRD2 gene; Data; Data Set; Dependence; Dopamine D2 Receptor; Drug Targeting; Electron Transport; Electrons; Experimental Models; FADH2; Freezing; Genetic Transcription; Germany; Goals; Grant; Human; In complete remission; Inner mitochondrial membrane; Lead; Literature; Maintenance; Manuscripts; Measures; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Matrix; Mitochondrial RNA; Molecular Analysis; Molecular Target; Monitor; NADH; Neoadjuvant Therapy; Operative Surgical Procedures; Oxidative Phosphorylation; Oxides; Parents; Pathologic; Patient-Focused Outcomes; Patient-derived xenograft models of breast cancer; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Platinum; Preparation; Primary Neoplasm; Process; Production; Prognosis; Proteins; Proteomics; Publishing; Pyruvate; Reaction; Refractory; Regimen; Relapse; Residual Cancers; Residual Tumors; Resistance; Ribosomes; Series; Translating; Translations; Tumor Volume; Validation; arm; base; chemotherapeutic agent; chemotherapy; clinical translation; cohort; docetaxel; efficacy testing; improved; in vivo; inhibitor; insight; interest; malignant breast neoplasm; mitochondrial genome; mitochondrial metabolism; multiple omics; novel; partial response; patient derived xenograft model; patient prognosis; pre-clinical; preclinical development; preclinical trial; proteogenomics; resistance mechanism; response; single-cell RNA sequencing; small molecule inhibitor; standard of care; targeted agent; targeted treatment; taxane; therapeutic target; transcriptomics; triple-negative invasive breast carcinoma; tumor

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.

项目摘要 本申请是为了响应特别利益通知（NOSI）而提交的，该通知被确定为 NOT-CA-22-039。 家长奖的总体目标是确定目标代理人，要么是有效的自己在三重 阴性乳腺癌（TNBC），或可以克服对常用一线化疗药物的耐药性 目前作为临床标准护理方案的一部分。我们对50个TNBC PDX的多组学分析 用化疗反应数据注释的模型将线粒体代谢确定为 与对多西他赛和卡铂的单独和组合的化学抗性相关的网络。也许 最重要的是，在42例接受多西他赛或卡铂单药治疗和联合治疗的PDX中，10例（24%） 未能对三种治疗中的任何一种显示出部分或完全反应，因此基本上完全 对这些药剂有抵抗力。我们对基线PDX组学的分子分析已经确定氧化磷酸化 （oxphos）和线粒体转录和翻译作为与对这两种抗性相关的主要过程 多西他赛和卡铂作为单一药剂，以及组合。我们在过去也得到了类似的结果 使用AC治疗的研究1.在对最近未发表的临床研究的分析中也观察到了类似的结果。 试验（CADENCE，NCT 02547987）。为了克服这种阻力，我们将测试两种新的药物的功效。 线粒体功能的小分子抑制剂，单独或与标准护理紫杉烷组合 或铂化疗剂。我们将在六个广泛表征的PDX中评估这些治疗方法 我们已经确定对单一和联合化疗治疗最具抗性的TNBC模型， 并且表达更高水平的两种药物靶点。LDC 204857（德国铅发现中心）是一个 线粒体RNA聚合酶抑制剂，从而抑制线粒体转录。这反过来又破坏了 电子传递链（ETC）和氧化磷酸化（oxphos）的产生。ONC206（Chimerix Inc） 是线粒体蛋白酶ClpP的激动剂和多巴胺受体D2的抑制剂，从而抑制ETC 超复杂组装和oxphos。我们已经在人类TNBC中积累了这些试剂的有希望的结果 细胞系和两者都准备好用于临床转化。