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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.

项目总结