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: 10476701
• 负责人: BALARAMAN KALYANARAMAN
• 金额: $ 42.26万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10476701
• 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; 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; efficacy evaluation; genetic approach; imaging modality; improved; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; innovation; lung cancer cell; 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。新有效的发展 迫切需要用于肺癌的化学预防剂。我们的长期目标是识别并推进新的目标 和针对人肺癌的有效预防剂。越来越多的证据表明肿瘤明显 特定的代谢变化，包括依赖有氧糖酵解和线粒体生物能学的变化， 是恶性肿瘤的关键驱动力。我们对甲胺（LON）进行了化学修饰，这是一种抗糖酵解 具有有限抗肿瘤功效的化合物，以更有效，更安全的线粒体形成线粒体。 具有新机制的靶向肿瘤细胞选择剂，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的有效抑制剂 生物能学，并导致明显缓解肺癌发展，细胞增殖，生长， 进展和转移。我们假设Mito-Lon抑制了肺部肿瘤的发展和转移 通过抑制线粒体复合物I和II的诱导自噬细胞死亡（ACD），耗尽 细胞ATP，刺激ROS的形成以及对AKT/MTOR/P70S6K信号传导的后续影响。我们将测试 我们以三个具体目标的假设。 AIM 1将确定线粒体生物能的影响 体外细胞系统中的氧化还原状态。 AIM 2将确定Mito-lon诱导ACD的能力，并以 侧重于线粒体，是减轻肺癌进展和转移的机制。 AIM 3将确定 Mito-lon抑制肺肿瘤进展和体内肺癌脑转移的能力。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）。这些目标的成功完成将 在肺癌抑制和更多情况下，提高我们对自噬的分子基础的理解 广泛建立一种使用线粒体靶向药物的新方法，以有效和有选择地阻止 癌细胞代谢，能量产生和诱导ACD。从未来开始，该提议是及时而重要的 MITO-LON针对肺癌的临床试验将需要对功效和 靶向癌症代谢的精确作用机制。