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: 10507157
• 负责人: Evan K. Noch
• 金额: $ 16.31万
• 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 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507157
• 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 Data; Clinical Trials; Combined Modality Therapy; Cysteine; Cysteine Metabolism Pathway; Cystine; Data; Dependence; Development Plans; 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; International; Intervention; 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; Pharmacology; Pharmacotherapy; Phase; Physicians; Positron-Emission Tomography; Pre-Clinical Model; Predisposition; Production; Pyruvate; Radiation; Reactive Oxygen Species; Reducing diet; Research; Research Personnel; Research Training; Role; Science; Scientist; Secure; Stress; System; Testing; The Cancer Genome Atlas; Toxic effect; 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; luciferin; metabolomics; molecular imaging; mouse model; neoplastic cell; neuro-oncology; neurotoxicity; novel; novel therapeutic intervention; pre-clinical; precision medicine; professor; response; skills; stress reduction; 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）是最终的标准GBM治疗方法之一。 （RT）和Temozolomide（TMZ）表现出较差的功效，缺乏耐用的反应 癌细胞中的氧化应激，这是GBM的已知代谢责任。 治疗受到神经毒性的限制和肿瘤逃生途径的上调，使氧化活性氧 物种。 GBM细胞中的途径，备用Spareng相邻的正常组织。 医师科学家神经肿瘤学家倾向于改善该私人的GBM治疗 神经胶质瘤中半胱氨酸敏感性途径的启发性促进性葡萄糖 依赖性，线粒体托作和H2O2产生，以定义机制和功能相关性 临床前模型中的这一途径。 诱导神经胶质瘤中的葡萄糖依赖性，半胱氨酸化合物与促进ROS的组合 治疗是提高GBM小鼠模型生存的有效策略。 胶质瘤中半胱氨酸改变的通量途径（AIM 1A）并确定线粒体电子转运的作用 链条通量（AIM 1B），缺氧和糖酵解通量（AIM 1C）有助于半胱氨酸介导的葡萄糖 使用GBM的小鼠模型，我将测试半胱氨酸半胱氨酸化合物 促进ROS促进干预措施（RT，TMZ和降糖生酮饮食）在GBM代谢，生长， 和生存，使用18F-氟丙基 - 双层半胱氨酸正电子发射断层扫描 代谢（AIM 2A）。 和促进ROS的干预措施（AIM 2B）体内将创建一个新的范式 可以迅速转化为GBM的早期临床试验的协同代谢疗法 Weill Cornell Medicine（WCM）神经肿瘤学系的神经病学助理教授， 我概述了一项为期5年的计划，该计划扩展了我的背景研究GBM代谢。 导师，刘易斯·坎特利（Lewis Cantley）博士，他是肿瘤代谢的专家，并能够翻译他的工作，并且 我的职业咨询委员会的临床开发工作包括刘易斯·坎特利（Lewis Cantley） 导师），Navdeep Chandel，Pedro Lowenstein，Naga Vara Kishore Pillarsetty，Howard Fine和Matthew 他们是国际公认的科学和医学专家，将提供指导 支持获得科学独立性。 是Cancelline的Precision Medicine取消的最前沿 医师科学家。 NIH R01将来的资金。 1