Mitochondrial metabolism as a target of breast cancer therapy

线粒体代谢作为乳腺癌治疗的目标

• 批准号: 10664934
• 负责人: ANTONINO PASSANITI
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664934
• 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; General Population; Genes; Genetic Transcription; Genus Hippocampus; Glucose; Glycolysis; Glycolysis Inhibition; 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; breast cancer diagnosis; breast cancer progression; cancer cell; cancer diagnosis; cancer stem cell; clinical efficacy; design; differential expression; drug development; drug discovery; drug efficacy; electron donor; improved; in vivo; inhibitor; 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; restraint; small molecule; small molecule inhibitor; stem; stem-like cell; targeted agent; targeted treatment; therapeutic target; therapeutically effective; tool; transcriptome; transcriptome sequencing; translational impact; translational potential; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor metabolism; tumor progression; whole genome

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.

乳腺癌（BC）是女性癌症死亡的最常见原因之一， 退伍军人事务部卫生保健系统中的女退伍军人发病率不断上升。患者生存率提高 对于原发性BC显著，但对于通常无法获得靶向药物的转移性BC是常见的 在非洲裔美国退伍军人，并在很大程度上无法治愈。大多数BC治疗靶向增殖的肿瘤细胞， 依靠糖酵解来满足新陈代谢的需要。然而，转移性BC可能表现出癌症干细胞表型， 具有相当大的休眠性和获得性耐药性。这些BC，包括三阴性BC（TNBC）， 通常依赖线粒体呼吸（氧化磷酸化; oxphos）产生能量， 促进生存。由于没有针对TNBC的靶向治疗，并且由于大多数靶向药物 显示出显著的毒性，因此需要找到新的和更安全的治疗剂。使用直接药物发现 方法和计算机辅助药物设计（CADD），我们确定了新的小分子，干扰 蛋白质：DNA结合和转录活性。虽然正常上皮细胞相对具有抵抗力，但铅 化合物（CADD 522）抑制BC细胞增殖和肿瘤球形成，延迟肿瘤生长， 体内转移，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。 了解靶向线粒体ATP合酶以提高ROS的分子机制 将可能导致针对转移性BC的新疗法。耐药、潜伏期 或转移性疾病可以受益于靶向线粒体oxphos的治疗方法， 抑制ATP合成酶。因此，我们提出了这样一个假设，即针对线粒体代谢， 一种新的ATP合酶抑制剂将通过降低ATP水平、减少肿瘤细胞的增殖、减少肿瘤细胞的增殖和转移， 细胞呼吸和增加ROS损伤以获得治疗益处。 特定目的-特定目的1：定义CADD 522介导的ATP合酶抑制的机制基础， 抑制BC肿瘤细胞增殖。线粒体耗氧率（OCR），整体基因表达 将定义ATP合酶的特征和直接靶向。具体目标2：通过以下方式确定机制 其中CADD 522介导的OCR抑制增加活性氧（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： 定义线粒体靶向CADD 522的翻译潜力，以促进ROS损伤并抑制 BC生长和转移。体外毒理学测定和体内肿瘤模型将评估翻译的 口服新治疗剂后的潜力。 总体影响-阐明重编程癌细胞代谢如何促进BC进展可能导致 预防或治疗转移性BC的策略。使用靶向肿瘤代谢需求的药物是一种有效的方法。 创新方法，并可能抑制涉及线粒体代谢的转移途径（茎样和/或 生长缓慢的肿瘤）。这些针对乳腺癌的方法将利用正常和 癌细胞，这可能最终对临床疗效和安全性产生影响。发现新的代谢产物 生物标志物将有助于患者分层和临床评价，从而为未来的研究提供强有力的理由。 研究性新药开发。总之，这些方法将是阐明 代谢靶向的翻译潜力，与VA医疗保健使命相关，并可能导致 为退伍军人转移性乳腺癌找到新的治疗方法

项目成果

Targeting breast cancer metabolism with a novel inhibitor of mitochondrial ATP synthesis.

使用线粒体 ATP 合成的新型抑制剂来靶向乳腺癌代谢。

• DOI: 10.18632/oncotarget.27743
• 发表时间: 2020-10-27
• 期刊: Oncotarget
• 作者: Kim MS;Gernapudi R;Cedeño YC;Polster BM;Martinez R;Shapiro P;Kesari S;Nurmemmedov E;Passaniti A
• 通讯作者: Passaniti A

Targeting mitochondrial metabolism for metastatic cancer therapy.

• DOI: 10.1002/mc.23436
• 发表时间: 2022-09
• 期刊: Molecular carcinogenesis
• 影响因子: 4.6