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）是最致命的人类癌症之一。标准 GBM 治疗，例如放射治疗 (RT) 和替莫唑胺 (TMZ) 的疗效较差，缺乏持久的反应。这些代理促进 癌细胞中的氧化应激是 GBM 的已知代谢负担。然而，这些方法的功效 治疗受到神经毒性和解毒活性氧的肿瘤逃逸途径上调的限制 物种。迫切需要有效针对氧化还原应激的新药物 GBM 细胞中的通路，同时不影响邻近的正常组织。我的长期目标是成为一个独立的人 神经肿瘤学家、科学家，专注于改善 GBM 治疗。在这个提案中，我使用了我的发现 神经胶质瘤中半胱氨酸敏感性途径的研究，半胱氨酸促进化合物诱导葡萄糖 依赖性、线粒体毒性和 H2O2 产生，以确定机制和功能相关性 该途径在临床前模型中的作用。我将检验中心假设，即高水平的细胞内半胱氨酸 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的组合 治疗是提高 GBM 小鼠模型存活率的有效策略。我将识别代谢 神经胶质瘤中半胱氨酸改变的通量途径（目标 1a）并确定线粒体电子传递的作用 链通量（目标 1b）以及缺氧和糖酵解通量（目标 1c）对半胱氨酸介导的葡萄糖的贡献 依赖性。使用 GBM 小鼠模型，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 代谢、生长、 和生存，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 H2O2 调节对半胱氨酸化合物细胞毒性的影响 以及体内 ROS 促进干预措施（目标 2b）。这些目标将创建一个新的范式，使用两个 可以快速转化为 GBM 早期临床试验的协同代谢疗法。我是一个 威尔康奈尔医学院 (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，该计划扩展了我研究 GBM 代谢的背景。我有一个优秀的 导师刘易斯·坎特利 (Lewis Cantley) 博士是肿瘤代谢方面的专家，并已将其工作成果翻译成英文 受训者的临床开发工作。我的职业咨询委员会包括博士。刘易斯·坎特利（小学 导师）、Navdeep Chandel、Pedro Lowenstein、Naga Vara Kishore Pillarsetty、Howard Fine 和 Matthew 芬克。他们是国际公认的科学和医学专家，将提供指导和帮助 支持实现科学独立。我还将获得 WCM 无与伦比的机构支持， 处于癌症精准医学的前沿，并大力投资于初级员工的职业发展 医生科学家。这种研究和培训环境将使我能够实现确保安全的目标 NIH R01 未来的资助。 1