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 该申请是为了响应特殊利益通知（NOSI）而提交 非CA-22-039。 父母奖的总体目标是确定目标代理人，这些代理人是单独有效的三倍 阴性乳腺癌（TNBC），或可以克服对常用第一线化学治疗药的耐药性 目前作为临床护理标准的一部分给出。我们的50 TNBC PDX的多摩尼克分析 用化学疗法反应数据注释的模型确定线粒体代谢是最重要的 与多西他赛和卡铂相关的网络，单独和组合。也许 最重要的是，在用单位药物多西他赛或卡铂处理的42个PDX中，组合为10（24％） 未能对三种治疗中的任何一个显示部分或完全反应，因此本质上完全是 对这些药物的抵抗力。我们对基线PDX OMICS的分子分析已鉴定出氧化磷酸化 （Oxphos）和线粒体转录和翻译作为与两者抗性相关的主要过程 多西他赛和卡铂作为单一代理以及组合。过去我们获得了类似的结果 使用AC处理的研究1。在对最近未发表的临床的分析中也观察到了类似的结果 试验（Cadence，NCT02547987）。为了克服这种抵抗，我们将测试两个小说的功效 线粒体功能的小分子抑制剂，无论是单独或与标准的紫杉烷 或铂化学疗法。我们将在六个广泛特征的PDX中评估这些处理 我们已经确定的TNBC模型对单一和联合化疗治疗最具耐药性， 并且表达了两个药物靶标的更高水平。 LDC204857（德国铅发现中心）是 线粒体RNA聚合酶的抑制剂，从而抑制线粒体转录。这反过 电子传输链（ETC）和氧化磷酸化（OXPHOS）的产生。 ONC206（Chimerix Inc） 是线粒体蛋白酶CLPP和多巴胺受体D2的抑制剂的激动剂，从而抑制 超复合组件和Oxphos。我们在人类TNBC中与这些药物相关的结果有希望的结果 细胞系和两者都可以进行临床翻译。