Unraveling glutamine metabolism in gliomas by PET imaging and biochemical methods

描述（由申请人提供）：该提案描述了一个五年的职业发展计划，目标是使Sriram Venneti博士能够晋升为独立的学术研究者和内科科学家。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Memorial Sloan-Kettering Cancer Center （MSKCC）从事研究奖学金。克雷格·汤普森博士是国际公认的癌症代谢专家，在培训临床医生和科学家方面有着良好的记录，他将是主要的导师。在神经胶质瘤研究方面享有盛誉的埃里克·霍兰德博士和癌症正电子发射断层扫描（PET）成像专家杰森·刘易斯博士将担任共同导师。此外，咨询委员会成员将提供科学和职业发展指导。该项目以Venneti博士之前的研究专长为基础，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、拨款写作和生物统计学方面进行进一步培训。MSKCC拥有丰富和协作的环境，以及对学员强有力的制度承诺。至少，文内蒂博士将获得75%的受保护研究时间。因此，MSKCC为Venneti博士提供了理想的环境，使他能够完成这个项目，过渡到一个独立资助的学术科学家。本研究的目的是揭示胶质瘤生存和增殖的核心代谢途径，并利用这些知识开发更有效的治疗策略和诊断成像方式。谷氨酰胺是人体中含量最丰富的氨基酸，是多种癌症中能量和大分子的重要来源；然而，在PI3K/AKT通路异常激活（如PDGFRA扩增和PTEN丢失的下游）或异柠檬酸脱氢酶1 （IDH1）突变驱动的胶质瘤中，谷氨酰胺是如何代谢的尚不清楚。我们通过提出谷氨酰胺代谢是胶质瘤发病机制的核心，以及18氟标记谷氨酰胺（18F-FGln）可用于PET在体内成像胶质瘤的总体假设，解决了我们知识中的这一重大空白。三个具体目标将检验这一假设。(1)在PDGFRA扩增/PTEN缺失或IDH1突变的胶质瘤动物模型中，使用谷氨酰胺类似物18F-FGln的PET成像来评估体内谷氨酰胺摄取。(2)在内源性PDGFRA扩增/PTEN缺失或IDH1突变的胶质瘤细胞系中，谷氨酰胺代谢将被确定。(3)通过谷氨酰胺酶和谷氨酸脱氢酶抑制谷氨酰胺代谢将在体外和体内被评估为对抗PDGFRA扩增/PTEN缺失或IDH1突变的胶质瘤的可行治疗靶点。这三个目标将共同促进一种新的、无创的PET成像方式的发展，以成像体内胶质瘤中的谷氨酰胺代谢，并确定谷氨酰胺代谢在胶质瘤发病机制中的作用，从而创造更有效的方法来治疗这些致命的肿瘤。

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.