Chemoprevention of lung cancer by targeting lonidamine to mitochondria

通过将氯尼达明靶向线粒体来化学预防肺癌

• 批准号: 9763831
• 负责人: BALARAMAN KALYANARAMAN
• 金额: $ 37.89万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763831
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; A/J Mouse; Address; Animals; Autophagocytosis; Bioenergetics; Brain; Cancer Etiology; Carboxylic Acids; Cell Compartmentation; Cell Death; Cell Line; Cell Proliferation; Cell model; Cessation of life; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Complex; Data; Development; Disease; Dose; Drug Targeting; Electron Transport; FRAP1 gene; Future; Generations; Goals; Growth; Human; In Vitro; Indazoles; Individual; Link; Lonidamine; Lung; Lung Neoplasms; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metastatic Neoplasm to the Lung; Metastatic malignant neoplasm to brain; Mitochondria; Modification; Molecular; Monitor; Mus; Neoplasm Metastasis; Oxidation-Reduction; Pathway interactions; Patients; Pattern; Pharmacology; Prevention strategy; Preventive; Primary Neoplasm; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Research; Signal Transduction; Stress; System; Testing; Time; Toxic effect; Tumor Burden; United States; aerobic glycolysis; analog; animal imaging; anti-cancer; bioluminescence imaging; brain tissue; cancer cell; carcinogenesis; design; genetic approach; imaging modality; improved; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; innovation; lung metastatic; lung tumorigenesis; mouse model; neoplastic cell; novel; novel strategies; peroxiredoxin; pre-clinical; preneoplastic cell; prevent; targeted agent; tumor; tumor metabolism; tumor progression

PROJECT SUMMARY Lung cancer is the leading cause of cancer death in the United States. The development of new and effective chemopreventive agents for lung cancer is urgently needed. Our long-term goal is to identify and advance new and efficacious preventive agents targeting human lung cancer. There is growing evidence that distinct tumor- specific metabolic changes, including reliance on aerobic glycolysis and changes in mitochondrial bioenergetics, are key drivers of malignancy. We made chemical modifications to lonidamine (LON), an anti-glycolytic compound with limited anti-tumor efficacy, to create Mito-LON as a more effective and safe mitochondria- targeted, tumor cell selective agent with a new mechanism, specifically OXPHOS inhibition. Our preliminary data show that Mito-LON, at low micromolar concentrations, is a potent inhibitor of cancer cell mitochondrial bioenergetics, and results in pronounced mitigation of lung cancer development, cell proliferation, growth, progression, and metastasis. We hypothesize that Mito-LON inhibits lung tumor development and metastasis through induction of autophagic cell death (ACD) by suppressing mitochondrial complexes I and II, depleting cellular ATP, stimulating ROS formation, and subsequent effects on AKT/mTOR/p70S6K signaling. We will test our hypothesis in three specific aims. Aim 1 will determine the effects of Mito-LON on mitochondrial bioenergetics and redox status in cellular systems in vitro. Aim 2 will determine the capacity of Mito-LON to induce ACD, with a focus on mitophagy, as a mechanism to mitigate lung cancer progression and metastasis. Aim 3 will determine the capacity of Mito-LON to inhibit lung tumor progression and lung cancer brain metastasis in vivo. We will use state-of-the-art small animal imaging to monitor the growth of primary tumors (using magnetic resonance imaging) and brain metastasis (through bioluminescence imaging). Successful completion of these aims will increase our understanding of the molecular basis of autophagy in the context of lung cancer inhibition and more broadly establish a new approach for using mitochondria-targeting drugs to effectively and selectively block cancer cell metabolism, energy generation, and induce ACD. This proposal is timely and significant since future clinical trials of Mito-LON against lung cancer will require vigorous preclinical characterization of the efficacy and precise mechanisms of action in targeting cancer metabolism.

项目摘要 肺癌是美国癌症死亡的主要原因。开发新的和有效的 肺癌的化学预防剂是迫切需要的。我们的长期目标是确定和推进新的 和靶向人肺癌的有效预防剂。越来越多的证据表明不同的肿瘤- 特定的代谢变化，包括对有氧糖酵解的依赖和线粒体生物能量学的变化， 是恶性肿瘤的关键驱动因素。我们对氯尼达明（LON）进行了化学修饰， 化合物具有有限的抗肿瘤功效，以创建Mito-LON作为更有效和安全的线粒体- 靶向的，肿瘤细胞选择性药物，具有新的机制，特别是OXPHOS抑制。我们的初步数据 表明Mito-LON在低微摩尔浓度下是癌细胞线粒体 生物能量学，并导致肺癌发展，细胞增殖，生长， 进展和转移。我们假设Mito-LON抑制肺肿瘤的发展和转移 通过抑制线粒体复合物I和II诱导自噬细胞死亡（ACD）， 细胞ATP，刺激ROS形成，以及随后对AKT/mTOR/p70 S6 K信号传导的影响。我们将测试 我们的假设有三个具体目标。目的1将确定Mito-LON对线粒体生物能量学的影响 和体外细胞系统中的氧化还原状态。目的2将确定Mito-LON诱导ACD的能力， 关注线粒体自噬，作为减缓肺癌进展和转移的机制。目标3将决定 Mito-LON在体内抑制肺肿瘤进展和肺癌脑转移的能力。我们将使用 最先进的小动物成像，以监测原发性肿瘤的生长（使用磁共振 成像）和脑转移（通过生物发光成像）。成功实现这些目标将 增加我们对肺癌抑制背景下自噬分子基础的理解， 广泛建立了一种新的方法，使用靶向药物，有效地和选择性地阻断 癌细胞代谢、能量生成，并诱导ACD。这一提议是及时的，也是未来的重要举措 Mito-LON抗肺癌的临床试验将需要有效的临床前表征， 靶向癌症代谢的精确作用机制。