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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肺癌是美国癌症死亡的主要原因。开发新的、有效的迫切需要肺癌的化学预防剂。我们的长期目标是识别和推进新的以及针对人类肺癌的有效预防剂。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，这是一种抗糖酵解药物抗肿瘤功效有限的化合物，以创建 Mito-LON 作为更有效和安全的线粒体 - 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量学，并显着减轻肺癌的发展、细胞增殖、生长、进展和转移。我们假设 Mito-LON 抑制肺部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/p70S6K 信号传导的影响。我们将测试我们的假设有三个具体目标。目标 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的氧化还原状态。目标 2 将确定 Mito-LON 诱导 ACD 的能力，其中重点关注线粒体自噬，作为减轻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）。成功完成这些目标将增加我们对肺癌抑制等背景下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有效和选择性阻断的新方法癌细胞代谢、能量产生并诱导ACD。这个建议非常及时，对于未来的发展也具有重要意义。 Mito-LON 治疗肺癌的临床试验需要对疗效和疗效进行严格的临床前表征。针对癌症代谢的精确作用机制。