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GBM治疗，如放射治疗 (RT)和替莫唑胺（TMZ），表现出较差的疗效，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GBM的已知代谢倾向。然而，这些药物的功效 治疗受到神经毒性和使活性氧解毒的肿瘤逃逸途径的上调的限制 物种迫切需要有效靶向氧化还原应激的新的药理学试剂 在GBM细胞中的信号通路，同时保留邻近的正常组织。我的长期目标是成为一个独立的 神经肿瘤学家专注于改善GBM治疗。在这个提议中，我用我的发现 胶质瘤中半胱氨酸易感性途径的研究，其中半胱氨酸促进化合物诱导葡萄糖 依赖性、线粒体毒性和H2 O2产生，以确定机制和功能相关性 在临床前的模型中。我将检验核心假设，即细胞内高水平的半胱氨酸 诱导神经胶质瘤中的葡萄糖依赖性，以及半胱氨酸化合物与促进ROS的 治疗是提高GBM小鼠模型存活率的有效策略。我会鉴定出 胶质瘤中半胱氨酸改变的通量途径（Aim 1a），并确定线粒体电子传递的作用 链通量（Aim 1b）和缺氧和糖酵解通量（Aim 1c）在半胱氨酸介导的葡萄糖 依赖使用GBM的小鼠模型，我将测试半胱氨酸化合物与 ROS促进干预（RT，TMZ和降糖生酮饮食）对GBM代谢，生长， 使用18F-氟丙基-高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 代谢（目标2a）。我将确定H2 O2调制对半胱氨酸化合物细胞毒性的影响 和ROS促进干预（目标2b）在体内。这些目标将创造一个新的范式， 协同代谢疗法，可以迅速转化为GBM的早期临床试验。我是一个 Weill Cornell Medicine（WCM）神经肿瘤科神经病学助理教授，以及 我已经概述了一个5年计划，扩大了我的背景研究GBM代谢。我有一个杰出的 导师，刘易斯坎特利博士，谁是肿瘤代谢方面的专家，并使他的工作， 临床开发的工作。我的职业顾问委员会包括刘易斯坎特利博士（主要 导师）、Navdeep Chandel、Pedro Lowenstein、那牙Vara Kishore Pillarsetty、霍华德Fine和Matthew 芬克他们是国际公认的科学和医学专家，将提供指导， 支持实现科学独立。我还将从WCM获得无与伦比的机构支持， 处于癌症精准医学的最前沿，并在初级职业发展方面投入巨资 物理科学家这种研究和培训环境将使我能够实现我的目标， R 01的未来。 1