Targeting Cysteine Susceptibility in Glioblastoma

靶向胶质母细胞瘤中的半胱氨酸敏感性

• 批准号: 10818812
• 负责人: Evan K. Noch
• 金额: $ 3.4万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10818812
• 关键词: Acetylcysteine; Advisory Committees; Amino Acids; Animal Model; Antibiotics; Biological Markers; Biology; Blood Glucose; Carbohydrates; Ceftriaxone; Cell Death; Cell Line; Cells; Chemotherapy and/or radiation; Clinical Trials; Combined Modality Therapy; Cysteine; Cysteine Metabolism Pathway; Cystine; Data; Dependence; Development Plans; Diet; Drug Metabolic Detoxication; Effectiveness; Electron Transport; Environment; Exhibits; Foundations; Funding; Future; Gene Expression; Glioblastoma; Glioma; Glucose; Glutamates; Glutathione; Goals; Growth; Homocysteine; Human; Hydrogen Peroxide; Hypoglycemic Agents; Hypoxia; Image; Institution; International; Intervention; Investments; Junior Physician; Malignant Neoplasms; Measures; Mediating; Medicine; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Methionine Metabolism Pathway; Mitochondria; Mus; NADP; Neurology; Normal tissue morphology; Oncologist; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pentosephosphate Pathway; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physicians; Positron-Emission Tomography; Pre-Clinical Model; Predisposition; Production; Pyruvate; Radiation; Reactive Oxygen Species; Reducing diet; Research; Research Personnel; Role; Science; Scientist; Secure; Stress; System; Testing; The Cancer Genome Atlas; Toxic effect; Training; Transgenic Organisms; Translating; Translations; Treatment Efficacy; Tumor Escape; Tumor Tissue; United States National Institutes of Health; Up-Regulation; Work; Xenograft procedure; cancer cell; career; career development; clinical development; combinatorial; cytotoxic; cytotoxicity; deprivation; early phase clinical trial; efficacy testing; enzyme activity; extracellular; glioma cell line; glucose metabolism; glucose uptake; improved; in vivo; ketogenic diet; ketogentic; luciferin; metabolomics; molecular imaging; mouse model; neoplastic cell; neuro-oncology; neurotoxicity; novel; novel therapeutic intervention; pharmacologic; pre-clinical; precision medicine; professor; response; skills; synergism; temozolomide; translational approach; tumor; tumor metabolism; uptake

Project Abstract Glioblastoma (GBM) is one of the most lethal human cancers. Standard GBM treatments, such as radiation (RT) and temozolomide (TMZ), exhibit poor efficacy with a lack of a durable response. These agents promote oxidative stress in cancer cells, which is a known metabolic liability of GBM. However, the efficacy of these treatments is limited by neurotoxicity and upregulation of tumor escape pathways that detoxify reactive oxygen species. There is an urgent need for new pharmacological agents that effectively target the redox stress pathway in GBM cells while sparing adjacent normal tissue. My long-term goal is to become an independent physician-scientist neuro-oncologist focused on improving GBM therapy. In this proposal, I use my discovery of a cysteine susceptibility pathway in glioma, whereby cysteine-promoting compounds induce glucose dependence, mitochondrial toxicity, and H2O2 production, to define the mechanism and functional relevance of this pathway in pre-clinical models. I will test the central hypothesis that high levels of intracellular cysteine induce glucose dependence in glioma, and the combination of cysteine compounds with ROS-promoting treatments is an effective strategy to improve survival in mouse models of GBM. I will identify the metabolic flux pathways altered by cysteine in glioma (Aim 1a) and determine the role of mitochondrial electron transport chain flux (Aim 1b) and hypoxia and glycolytic flux (Aim 1c) in contributing to cysteine-mediated glucose dependence. Using mouse models of GBM, I will test the efficacy of cysteine compounds in combination with ROS-promoting interventions (RT, TMZ, and the glucose-lowering ketogenic diet) on GBM metabolism, growth, and survival, using 18F-fluoropropyl-homocysteine positron emission tomography as a biomarker for cysteine metabolism (Aim 2a). I will determine the effects of H2O2 modulation on cytotoxicity of cysteine compounds and ROS-promoting interventions (Aim 2b) in vivo. These aims will create a new paradigm that uses two synergistic metabolic therapies that can be rapidly translated into early-phase clinical trials in GBM. I am an Assistant Professor in Neurology within the Division of Neuro-Oncology at Weill Cornell Medicine (WCM), and I have outlined a 5-year plan that expands on my background studying GBM metabolism. I have an outstanding mentor, Dr. Lewis Cantley, who is an expert in tumor metabolism and has enabled translation of his work and mentees’ work to clinical development. My career advisory committee includes Drs. Lewis Cantley (primary mentor), Navdeep Chandel, Pedro Lowenstein, Naga Vara Kishore Pillarsetty, Howard Fine, and Matthew Fink. They are internationally recognized experts in science and medicine and will provide mentorship and support to attain scientific independence. I will also have unparalleled institutional support from WCM, which is at the forefront of precision medicine in cancer and is heavily invested in career development for junior physician-scientists. This research and training environment will enable me to achieve my goals of securing NIH R01 funding in the future. 1

项目摘要 胶质母细胞瘤(GBM)是人类最致命的癌症之一。标准的GBM治疗，如辐射 (RT)和替莫唑胺(TMZ)的疗效较差，缺乏持久的反应。这些代理商促进 癌细胞中的氧化应激，这是已知的GBM的代谢易感性。然而，这些药物的功效 治疗受到神经毒性和肿瘤逃逸途径上调的限制，这些途径可以解毒活性氧。 物种。迫切需要有效地针对氧化还原压力的新的药理学药物。 在GBM细胞中的途径，而保留邻近的正常组织。我的长期目标是成为一名独立的 内科医生兼科学家、神经肿瘤学家专注于改进GBM治疗。在这个提案中，我用我的发现 胶质瘤中半胱氨酸易感途径的研究，半胱氨酸促进剂通过该途径诱导葡萄糖 依赖、线粒体毒性和过氧化氢的产生，以确定其机制和功能相关性 在临床前模型中对这一途径的研究。我将测试中心假设，细胞内高水平的半胱氨酸 诱导胶质瘤对葡萄糖的依赖，以及半胱氨酸化合物与ROS促进剂的结合 治疗是提高小鼠GBM模型存活率的有效策略。我会确定新陈代谢 半胱氨酸改变脑胶质瘤中的通量通路(Aim 1a)并确定线粒体电子传递的作用 链通量(目标1b)和缺氧和糖酵解通量(目标1c)对半胱氨酸介导的葡萄糖的贡献 依赖。利用小鼠的GBM模型，我将测试半胱氨酸化合物与 促进ROS的干预措施(RT、TMZ和降糖生酮饮食)对GBM的代谢、生长、 使用18F-氟丙基-同型半胱氨酸正电子发射断层扫描作为半胱氨酸的生物标志物 新陈代谢(目标2a)。我将确定H_2O_2对半胱氨酸化合物细胞毒性的调节作用 和体内促进ROS的干预措施(Aim 2b)。这些目标将创建一种新的范式，使用两个 可迅速转化为GBM早期临床试验的协同代谢疗法。我是一个 威尔·康奈尔医学(WCM)神经肿瘤学部神经病学助理教授 我已经概述了一个五年计划，它扩展了我研究GBM新陈代谢的背景。我有一个杰出的 导师刘易斯·坎特利博士是肿瘤新陈代谢方面的专家，并已将他的工作和 指导对象的工作对临床发展的影响。我的职业顾问委员会包括刘易斯·坎特利博士(主要 导师)，纳夫迪普·香德尔，佩德罗·洛文斯坦，纳加瓦拉·基肖尔·皮拉塞蒂，霍华德·费恩和马修 芬克。他们是国际公认的科学和医学专家，将提供指导和 支持实现科学独立。我还将得到WCM无与伦比的机构支持，这 处于癌症精准医学的前沿，并在青少年的职业发展上投入了大量资金 内科医生-科学家。这种研究和培训环境将使我能够实现我的目标 NIH R01未来的资金来源。 1