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.

项目概要 本申请是为了响应特殊利益通知（NOSI）而提交的，该通知被确定为 不是-CA-22-039。 家长奖的总体目标是确定单独有效的靶向药物 阴性乳腺癌 (TNBC)，或可以克服对常用一线化疗药物的耐药性 目前作为临床护理方案标准的一部分提供。我们对 50 个 TNBC PDX 进行多组学分析 用化疗反应数据注释的模型将线粒体代谢确定为最重要的代谢途径之一 与多西紫杉醇和卡铂单独和组合的化学耐药性相关的网络。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，有 10 例 (24%) 未能对三种治疗中的任何一种表现出部分或完全反应，因此基本上完全有效 对这些药剂有抵抗力。我们对基线 PDX 组学的分子分析发现了氧化磷酸化 (oxphos) 和线粒体转录和翻译是与两者抗性相关的主要过程 多西紫杉醇和卡铂可以作为单药，也可以联合用药。我们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类似的结果 试验（CADENCE，NCT02547987）。为了克服这种阻力，我们将测试两种新颖的功效 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 或铂类化疗药物。我们将在六种广泛表征的 PDX 中评估这些治疗方法 我们已确定对单一和联合化疗最耐药的 TNBC 模型， 并且表达了两种药物靶标的更高水平。 LDC204857（德国领先发现中心）是一个 线粒体RNA聚合酶抑制剂，从而抑制线粒体转录。这反过来又扰乱了 电子传递链（ETC）和氧化磷酸化（oxphos）的产生。 ONC206（Chimerix 公司） 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 超级复杂的组装和oxphos。我们使用这些药物在人类 TNBC 中取得了有希望的结果 细胞系均已准备好进行临床转化。