Unraveling glutamine metabolism in gliomas by PET imaging and biochemical methods

通过 PET 成像和生化方法揭示神经胶质瘤中的谷氨酰胺代谢

• 批准号: 8617905
• 负责人: Sriram Venneti
• 金额: $ 8.01万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2014-10-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617905
• 关键词: ATP Synthesis Pathway; Address; Adult; Advisory Committees; Amino Acids; Anatomy; Animal Model; Animals; Applications Grants; Biochemical; Bioenergetics; Biometry; Brain Neoplasms; Brain imaging; Cell Line; Cells; Citric Acid Cycle; Clinical; Collaborations; Data; Detection; Development; Development Plans; Diagnosis; Diagnostic; Diagnostic Imaging; Energy-Generating Resources; Environment; Enzymes; Epidermal Growth Factor Receptor; Exhibits; Fellowship; Figs - dietary; Fumarates; Funding; Genetic; Glioblastoma; Glioma; Glutamate Dehydrogenase; Glutaminase; Glutamine; Goals; Grant; Growth; Health; Hypoxia; Image; Implant; In Vitro; Isocitrate Dehydrogenase; Knockout Mice; Knowledge; Label; Lipids; Malates; Malignant - descriptor; Malignant Neoplasms; Memorial Sloan-Kettering Cancer Center; Mentors; Metabolic; Metabolic Pathway; Metabolism; Methods; Modality; Monitor; Mus; Mutation; Non-Invasive Cancer Detection; Nutrient; Oncogenes; PDGFRA gene; PI3K/AKT; PTEN gene; Pathogenesis; Pathology; Pathway interactions; Pennsylvania; Physicians; Plasma; Play; Positron-Emission Tomography; Production; Proliferating; Proteins; Radiation; Research; Research Ethics; Research Personnel; Role; Scientist; Sensitivity and Specificity; Signal Transduction; Specificity; Testing; Therapeutic; Time; Training; Training and Education; Translating; Treatment Efficacy; Tumor Biology; Tumor Pathology; Universities; Work; Writing; cancer cell; cancer type; career; career development; chemotherapy; combat; design; effective therapy; fluorodeoxyglucose; glioma cell line; glutamine analog; imaging modality; in vivo; insight; macromolecule; member; mouse model; neuroinflammation; neuropathology; non-invasive imaging; novel; nutrient metabolism; outcome forecast; programs; research study; therapeutic target; tumor; tumor metabolism; uptake

DESCRIPTION (provided by applicant): This proposal describes a 5-year career development plan with the goal of enabling Dr. Sriram Venneti to advance to the role of independent academic investigator and physician-scientist. Dr. Venneti has completed his clinical training in Anatomic Pathology and Neuropathology at the University of Pennsylvania and is currently engaged in a research fellowship at Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Craig Thompson, an internationally recognized expert on cancer metabolism with a strong record of training clinician- scientists, will be the principle mentor. Dr. Eric Holland, renowned or his work in gliomas, and Dr. Jason Lewis, an expert in positron emission tomography (PET) imaging in cancer, will serve as co-mentors. Additionally, members of the advisory committee will provide scientific and career development guidance. This project builds on Dr. Venneti's previous research expertise and proposes further training in cancer metabolism, small animal PET imaging, brain tumor biology, research ethics, grant writing and biostatistics, by means of investigative research and formal course work. MSKCC has a rich and collaborative environment, and a strong institutional commitment to its trainees. At a minimum, Dr. Venneti will be provided with 75% protected research time. MSKCC thus provides the ideal setting for Dr. Venneti to carry out this program to transition to an independently funded academic scientist. The goal of this research is to unravel core metabolic pathways that gliomas use to survive and proliferate and to use this knowledge to develop more effective therapeutic strategies and diagnostic imaging modalities. Glutamine is the most abundant amino acid in the body and is an essential source of energy and macromolecules in many types of cancer; however, how glutamine is metabolized in gliomas driven by aberrant PI3K/AKT pathway activation (such as downstream of PDGFRA amplification and PTEN loss) or isocitrate dehydrogenase 1 (IDH1) mutations is not clearly understood. We address this significant gap in our knowledge by proposing the overall hypothesis that glutamine metabolism is central to the pathogenesis of gliomas and that 18fluorine-labeled glutamine (18F-FGln) can be used to image gliomas in vivo using PET. Three specific aims will test this hypothesis. (1) Glutamine uptake will be evaluated in vivo using PET imaging with the glutamine analogue 18F-FGln in glioma animal models with PDGFRA amplification/PTEN loss or IDH1 mutations. (2) Glutamine metabolism will be determined in glioma cells lines bearing endogenous PDGFRA amplification/PTEN loss or IDH1 mutations. (3) Inhibition of glutamine metabolism by targeting the enzymes glutaminase and glutamate dehydrogenase will be evaluated as a viable therapeutic target for combatting gliomas with PDGFRA amplification/PTEN loss or IDH1 mutations in vitro and in vivo. These three aims together will enable development of a novel, non-invasive PET imaging modality to image glutamine metabolism in gliomas in vivo and to ascertain the role played by glutamine metabolism in the pathogenesis of gliomas, so as to create more effective ways to treat these deadly tumors.

描述（由申请人提供）：该提案描述了一个 5 年职业发展计划，旨在使 Sriram Venneti 博士晋升为独立学术研究者和医师科学家。 Venneti 博士在宾夕法尼亚大学完成了解剖病理学和神经病理学的临床培训，目前在纪念斯隆-凯特琳癌症中心 (MSKCC) 从事研究工作。克雷格·汤普森 (Craig Thompson) 博士是国际公认的癌症代谢专家，在培训临床医生-科学家方面拥有丰富的经验，他将担任首席导师。在神经胶质瘤领域享有盛誉的 Eric Holland 博士和癌症正电子发射断层扫描 (PET) 成像专家 Jason Lewis 博士将担任联合导师。此外，咨询委员会成员还将提供科学和职业发展指导。该项目以 Venneti 博士之​​前的研究专业知识为基础，并建议通过调查研究和正式课程作业，在癌症代谢、小动物 PET 成像、脑肿瘤生物学、研究伦理、资助写作和生物统计学方面进行进一步培训。 MSKCC 拥有丰富的协作环境，以及对其学员强有力的制度承诺。 Venneti 博士将至少获得 75% 受保护的研究时间。因此，MSKCC 为 Venneti 博士实施该项目提供了理想的环境，以过渡为独立资助的学术科学家。这项研究的目标是揭示神经胶质瘤生存和增殖的核心代谢途径，并利用这些知识来开发更有效的治疗策略和诊断成像方式。谷氨酰胺是体内最丰富的氨基酸，是多种癌症中能量和大分子的重要来源；然而，谷氨酰胺在异常 PI3K/AKT 通路激活（例如 PDGFRA 扩增下游和 PTEN 丢失）或异柠檬酸脱氢酶 1 (IDH1) 突变驱动的神经胶质瘤中的代谢尚不清楚。我们通过提出总体假设来解决我们知识中的这一重大差距，即谷氨酰胺代谢是神经胶质瘤发病机制的核心，并且 18 氟标记的谷氨酰胺 (18F-FGln) 可用于使用 PET 对神经胶质瘤进行体内成像。三个具体目标将检验这一假设。 (1) 在具有 PDGFRA 扩增/PTEN 缺失或 IDH1 突变的神经胶质瘤动物模型中，使用谷氨酰胺类似物 18F-FGln 进行 PET 成像，在体内评估谷氨酰胺的摄取。 (2) 将在具有内源性 PDGFRA 扩增/PTEN 缺失或 IDH1 突变的神经胶质瘤细胞系中测定谷氨酰胺代谢。 (3) 通过靶向谷氨酰胺酶和谷氨酸脱氢酶来抑制谷氨酰胺代谢，将被评估为体外和体内对抗 PDGFRA 扩增/PTEN 缺失或 IDH1 突变的神经胶质瘤的可行治疗靶点。这三个目标共同将有助于开发一种新型非侵入性 PET 成像方式，对胶质瘤体内的谷氨酰胺代谢进行成像，并确定谷氨酰胺代谢在胶质瘤发病机制中所起的作用，从而创造更有效的方法来治疗这些致命的肿瘤。