Mitochondrial metabolism as a target of breast cancer therapy

线粒体代谢作为乳腺癌治疗的目标

基本信息

批准号：
10174751
负责人：
ANTONINO PASSANITI
金额：
--
依托单位：
BALTIMORE VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10174751
关键词：
Adenosine Triphosphate African American Antioxidants Biological Assay Biological Markers Breast Cancer Cell Breast Cancer Treatment Breast Cancer therapy Breast cancer metastasis Cancer Cell Growth Cancer Etiology Cell Culture Techniques Cell Proliferation Cell Respiration Cells Cessation of life Citrates Citric Acid Cycle Clinical Computer Assisted DNA-Binding Proteins Data Diagnosis Disease Drug Design Drug Kinetics Drug Targeting Drug resistance Drug toxicity Electron Transport Epithelial Cells Equilibrium Exhibits FADH2 Future Genes Genetic Transcription Genus Hippocampus Glucose Glycolysis Goals Growth Healthcare Healthcare Systems Hybrids Hypoxia In Vitro Incidence Investigational Drugs Lead Malignant Neoplasms Mammospheres Measures Mediating Metabolic Metabolic Pathway Metastatic breast cancer Mission Mitochondria Modeling Molecular Mutation NADH Neoplasm Metastasis Normal Cell Nutritional Oral Oral Administration Outcome Oxidation-Reduction Oxidative Phosphorylation Oxygen Consumption Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Production Proliferating Reactive Oxygen Species Regulation Resistance Respiration Role Safety Signal Transduction Therapeutic Therapeutic Agents Toxic effect Toxicology Transcriptional Regulation Tricarboxylic Acids Veterans Woman acquired drug resistance base breast cancer diagnosis breast cancer progression cancer cell cancer diagnosis cancer drug resistance cancer stem cell clinical efficacy design differential expression drug development drug discovery drug efficacy electron donor improved in vivo inhibitor/antagonist innovation malignant breast neoplasm men mitochondrial metabolism mouse model neoplastic cell novel novel therapeutics oxidative damage patient derived xenograft model patient stratification preclinical development prevent pyruvate dehydrogenase research clinical testing response small molecule small molecule inhibitor stem stem-like cell targeted agent targeted treatment therapeutic target therapeutically effective tool transcriptome transcriptome sequencing translational impact triple-negative invasive breast carcinoma tumor tumor growth tumor metabolism tumor progression whole genome

Adenosine Triphosphate African American Antioxidants Biological Assay Biological Markers Breast Cancer Cell Breast Cancer Treatment Breast Cancer therapy Breast cancer metastasis Cancer Cell Growth Cancer Etiology Cell Culture Techniques Cell Proliferation Cell Respiration Cells Cessation of life Citrates Citric Acid Cycle Clinical Computer Assisted DNA-Binding Proteins Data Diagnosis Disease Drug Design Drug Kinetics Drug Targeting Drug resistance Drug toxicity Electron Transport Epithelial Cells Equilibrium Exhibits FADH2 Future Genes Genetic Transcription Genus Hippocampus Glucose Glycolysis Goals Growth Healthcare Healthcare Systems Hybrids Hypoxia In Vitro Incidence Investigational Drugs Lead Malignant Neoplasms Mammospheres Measures Mediating Metabolic Metabolic Pathway Metastatic breast cancer Mission Mitochondria Modeling Molecular Mutation NADH Neoplasm Metastasis Normal Cell Nutritional Oral Oral Administration Outcome Oxidation-Reduction Oxidative Phosphorylation Oxygen Consumption Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Production Proliferating Reactive Oxygen Species Regulation Resistance Respiration Role Safety Signal Transduction Therapeutic Therapeutic Agents Toxic effect Toxicology Transcriptional Regulation Tricarboxylic Acids Veterans Woman acquired drug resistance base breast cancer diagnosis breast cancer progression cancer cell cancer diagnosis cancer drug resistance cancer stem cell clinical efficacy design differential expression drug development drug discovery drug efficacy electron donor improved in vivo inhibitor/antagonist innovation malignant breast neoplasm men mitochondrial metabolism mouse model neoplastic cell novel novel therapeutics oxidative damage patient derived xenograft model patient stratification preclinical development prevent pyruvate dehydrogenase research clinical testing response small molecule small molecule inhibitor stem stem-like cell targeted agent targeted treatment therapeutic target therapeutically effective tool transcriptome transcriptome sequencing translational impact triple-negative invasive breast carcinoma tumor tumor growth tumor metabolism tumor progression whole genome

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项目摘要

Significance – Breast cancer (BC) is one of the most common causes of cancer deaths for women with increasing incidence among women Veterans in the VA Health Care System. Patient survival has improved dramatically for primary BC but metastatic BC, for which targeted agents are usually not available, is common in African-American Veterans and is largely incurable. Most BC treatments target proliferating tumor cells that rely on glycolysis to fuel their metabolic needs. However, metastatic BC may exhibit a cancer stem cell phenotype with considerable dormancy and acquired drug resistance. These BC, including triple negative BC (TNBC), are often dependent on mitochondrial respiration (oxidative phosphorylation; oxphos) to generate energy and promote survival. Since there are no targeted therapies for TNBC and since most mitochondrial-targeting drugs exhibit substantial toxicity, there is a need to find new and safer therapeutic agents. Using a direct drug discovery approach and computer-assisted drug design (CADD), we identified novel small molecules that interfere with protein:DNA binding and transcriptional activity. While normal epithelial cells were relatively resistant, a lead compound (CADD522) inhibited BC cell proliferation and tumorsphere formation, delayed tumor growth and metastasis in vivo, and inhibited mitochondrial adenosine triphosphate (ATP) synthase and respiration (oxygen consumption) while increasing the levels of reactive oxygen species (ROS). Premise – Understanding the molecular mechanisms of targeting mitochondrial ATP synthase to elevate ROS in cancer cells will likely result in novel therapeutics against metastatic BC. Patients with drug-resistant, dormant or metastatic disease could benefit from a therapeutic approach that targets mitochondrial oxphos by inhibiting ATP synthase. Therefore, we propose the hypothesis that targeting mitochondrial metabolism with a novel ATP synthase inhibitor will inhibit BC tumor progression and metastasis by lowering ATP levels, reducing cellular respiration, and increasing ROS damage for therapeutic benefit. Specific Aims – Specific Aim 1: Define the mechanistic basis for CADD522-mediated ATP synthase inhibition in restraining BC tumor cell proliferation. Mitochondrial oxygen consumption rate (OCR), global gene expression profiles and direct targeting of ATP synthase will be defined. Specific Aim 2: Determine the mechanisms through which CADD522-mediated OCR inhibition increases reactive oxygen species (ROS) to reduce glucose utilization. Redox balance, pyruvate dehydrogenase (PDH) activity, and TCA cycle flux will be measured. Specific Aim 3: Define the translational potential of mitochondrial targeting with CADD522 to promote ROS damage and inhibit BC growth and metastasis. In vitro toxicological assays and in vivo tumor models will assess translational potential after oral administration of a novel therapeutic agent. Overall Impact – Elucidating how reprogrammed cancer cell metabolism promotes BC progression may lead to strategies to prevent or treat metastatic BC. Using agents that target a tumor’s metabolic requirements is an innovative approach and may inhibit metastatic pathways involving mitochondrial metabolism (stem-like and/or slow-growing tumors). These mitochondria-targeted approaches will exploit differences between normal and cancer cells, which may ultimately have an impact on clinical efficacy and safety. Discovery of new metabolic biomarkers will aid in patient stratification and clinical evaluation thus providing strong justification for future investigational new drug development. In summary, these approaches will be fundamental in elucidating the translational potential of metabolic targeting, are of relevance to the VA health care mission, and will likely lead to the discovery of new treatments for Veterans with metastatic BC.

意义 - 乳腺癌（BC）是癌症死亡的最常见原因之一 VA卫生保健系统中女退伍军人的发病率增加。患者生存有所改善对于主要卑诗省的动态而动态的，但对于通常不可用的靶向剂的转移性BC是常见的在非裔美国退伍军人中，基本上是无法治愈的。大多数卑诗省治疗目标是针对增生的肿瘤细胞依靠糖酵解来促进其代谢需求。但是，BC转移性可能会退出癌症干细胞表型具有可考虑的休眠和获得的耐药性。这些BC，包括三重负BC（TNBC），是通常取决于线粒体呼吸（氧化磷酸化； Oxphos）产生能量和促进生存。由于没有针对TNBC的靶向疗法，而且大多数线粒体靶向药物表现出很大的毒性，需要找到新的，更安全的治疗剂。使用直接药物发现方法和计算机辅助的药物设计（CADD），我们确定了干扰的新型小分子蛋白质：DNA结合和转录活性。虽然正常的上皮细胞相对抗性，但铅化合物（CADD522）抑制了BC细胞增殖和肿瘤形成，肿瘤生长延迟转移体内，并抑制线粒体三磷酸腺苷（ATP）合酶和呼吸（氧消耗）同时增加活性氧（ROS）的水平。前提 - 了解靶向线粒体ATP合酶升高ROS的分子机制在癌细胞中，可能会导致针对BC转移性的新疗法。耐药性，休眠的患者或转移性疾病可能受益于针对线粒体oxphos的治疗方法抑制ATP合酶。因此，我们提出了以下假设：靶向线粒体代谢一种新型的ATP合酶抑制剂将通过降低ATP水平抑制BC肿瘤的进展和转移细胞呼吸，并增加ROS损伤以获得治疗益处。具体目的 - 特定目标1：定义CADD522介导的ATP合酶抑制的机械基础限制BC肿瘤细胞增殖。线粒体氧的消耗率（OCR），全球基因表达将定义ATP合酶的轮廓和直接靶向。特定目标2：通过 CADD522介导的OCR抑制会增加活性氧（ROS）以减少葡萄糖利用。将测量氧化还原平衡，丙酮酸脱氢酶（PDH）活性和TCA循环通量。具体目标3：定义用CADD522靶向线粒体靶向的翻译潜力，以促进ROS损伤并抑制 BC生长和转移。体外毒理学评估和体内肿瘤模型将评估翻译口服新型治疗剂后的潜力。总体影响 - 阐明重编程的癌细胞代谢如何促进BC的进展可能导致预防或治疗转移性BC的策略。使用针对肿瘤代谢需求的代理是一种创新方法并可能抑制转移途径涉及线粒体代谢（类似于茎状和/或生长缓慢的肿瘤）。这些以线粒体为目标的方法将利用正常和癌细胞最终可能会对临床效率和安全产生影响。发现新代谢生物标志物将有助于患者分层和临床评估，从而为未来提供强有力的理由研究新药开发。总而言之，这些方法将是阐明代谢靶向的转化潜力，与VA医疗保健任务相关，可能会领导为通过转移性卑诗省的退伍军人发现新疗法。