Novel PET imaging agents for understanding glutamine addiction in cancer

用于了解癌症中谷氨酰胺成瘾的新型 PET 成像剂

• 批准号: 8231824
• 负责人: LEWIS A CHODOSH
• 金额: $ 81.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231824
• 关键词: 2-Fluoro-2-deoxyglucose; Acute; Amino Acids; Biodistribution; Biological; Biological Markers; Cancer Biology; Cancer Patient; Cell Death; Cells; Clinic; Collaborations; Computational Biology; Dependence; Detection; Development; Diagnosis; Down-Regulation; ERBB2 gene; Energy-Generating Resources; Enzymes; Evaluation; Exhibits; Gene Expression; Genetic; Genetically Engineered Mouse; Glucose; Glutamine; Glycolysis; Human; Image; Imaging Device; Imaging technology; In Vitro; Individual; Label; Laboratories; Lead; Malignant Neoplasms; Maps; Mediating; Metabolic; Metabolic Marker; Metabolic Pathway; Metabolic stress; Metabolism; Methods; Modeling; Modification; Molecular; Molecular Target; Monitor; Mus; Nutrient; Nutritional; Oncogenes; Oncogenic; Paper; Pathway interactions; Pennsylvania; Positron-Emission Tomography; Preparation; Radiopharmaceuticals; Reporting; Research; Role; Science; Series; Signal Pathway; Source; Specificity; System; Systems Biology; Testing; Tracer; Transgenic Mice; Translations; Tumor Cell Line; Universities; Up-Regulation; addiction; antitumor agent; base; c-myc Genes; cancer cell; cancer imaging; cancer therapy; cellular targeting; clinically relevant; in vivo; malignant breast neoplasm; molecular imaging; mouse model; neoplastic cell; novel; overexpression; preference; programs; ras Oncogene; response; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): Based on the needs of the proposed integrated research a multiple-PI project will be used to maximize the potential of "team science" efforts on understanding of changes of cancer metabolism. The collaboration between Chosdosh and Kung labs in the University of Pennsylvania will provide a platform for integration of advanced in vivo PET imaging technologies with system biology approaches to understand in vivo imaging of cancer. The objective of this project is to prepare and evaluate 18F labeled glutamine derivatives for diagnosis of tumor growth in cancer patients and to investigate the cancer biology associated with the uptake of the novel tracers in cancer cells. In conjunction with positron emission tomography (PET) these new probes may provide imaging tools for studying re-programming of metabolic pathways for producing energy and building blocks to sustain proliferation of tumor cells. Due to changing nutrient needs associated to tumor metabolism and proliferation, there is a tumor specific increase in glycolysis and coordinated changes gene expression to maintain a high rate of metabolism. The increase in glycolysis in major tumor types has been demonstrated by FDG-PET. However, there is a significant fraction of active tumors that shows a negative FDG uptake suggesting that the FDG-negative tumors may be using alternative sources of energy and nutrient, such as glutamine and other amino acids. Recent reports indicate that there are tumor cells, such as SF188 cells that display a high c-myc gene expression, which leads to a high level of glutaminolysis. Reprogramming of genetic expression, up-regulation of the oncogenes, such as c-Myc, HER2/neu, Wnt, Ras and Akt, and shifting of the energy source associated with the proposed probes of tumor glutaminolysis and FDG-PET will be evaluated. We will develop methods to prepare a series of 18F labeled glutamines and specific fine-tuning of the oncogene expression in transgenic mice. The glutamines will be tested in tumor cells, such as 9L, C6, PC3 and SF188 cells, which have demonstrated propensity for higher amino acid uptake and glutaminolysis. Additionally, the tumor cell uptake will be correlated with oncogene expression through the use of conditional transgenic mouse models for c-MYC, HER2/neu, Wnt1, Ras and Akt overexpressing breast cancers. Successful glutamine imaging agents will be selected for PET imaging of transgenic mice the tumors, in which metabolic changes showing preference in using glutamine derivatives as the main source of nutrient. The proposed 18F labeled glutamines may serve as new metabolic markers for probing glutamine-addictive tumors not detected by FDG-PET. The development of the proposed alternative metabolic biomarkers provides an exciting opportunity for advancing diagnosis and treatment of tumor. The novel tumor metabolic imaging agents may lead to new methods to appraise the metabolic status of tumor growth in human cancer and provide advancement of our understanding of tumor oncogene expression and tumor metabolism by PET imaging.

描述(由申请人提供)：基于拟议的综合研究的需要，将使用一个多PI项目来最大限度地发挥“团队科学”在了解癌症新陈代谢变化方面的潜力。宾夕法尼亚大学Chosdosh和Kung实验室之间的合作将提供一个平台，将先进的活体PET成像技术与系统生物学方法相结合，以了解癌症的活体成像。本项目的目的是制备和评价18F标记的谷氨酰胺衍生物，用于癌症患者肿瘤生长的诊断，并研究与新型示踪剂在癌细胞中摄取相关的癌症生物学。与正电子发射断层扫描(PET)相结合，这些新的探针可能为研究代谢途径的重新编程提供成像工具，以产生能量和构建维持肿瘤细胞增殖的积木。由于与肿瘤代谢和增殖相关的营养需求不断变化，肿瘤特异性糖酵解和协同变化基因表达增加，以维持较高的新陈代谢速率。FDG-PET显示主要肿瘤类型的糖酵解增加。然而，有相当一部分活动性肿瘤显示FDG摄取为阴性，这表明FDG阴性的肿瘤可能正在使用替代的能量和营养来源，如谷氨酰胺和其他氨基酸。最近的报道表明，一些肿瘤细胞，如SF188细胞，表现出高水平的c-myc基因表达，从而导致高水平的谷氨酰胺分解。将评估基因表达的重新编程、癌基因如c-Myc、HER2/neu、Wnt、RAS和Akt的上调，以及与拟议的肿瘤谷氨酰胺溶解和FDG-PET相关的能源转移。我们将开发一系列18F标记谷氨酸的制备方法，并在转基因小鼠中对癌基因表达进行特异性微调。谷氨酰胺将在肿瘤细胞中进行测试，如9L、C6、PC3和SF188细胞，这些细胞表现出更高的氨基酸摄取和谷氨酰胺分解倾向。此外，通过使用c-myc、HER2/neu、Wnt1、RAS和Akt过表达乳腺癌的条件转基因小鼠模型，肿瘤细胞的摄取将与癌基因表达相关。成功的谷氨酰胺显像剂将被选择用于转基因小鼠肿瘤的PET成像，其中代谢变化显示出倾向于使用谷氨酰胺衍生物作为主要营养来源。所提出的18F标记谷氨酸可作为新的代谢标志物用于探测FDG-PET未检测到的谷氨酰胺成瘾肿瘤。新陈代谢生物标志物的发展为促进肿瘤的诊断和治疗提供了一个令人振奋的机会。新的肿瘤代谢显像剂可能为评价肿瘤生长的代谢状态提供新的方法，并通过PET成像促进我们对肿瘤癌基因表达和肿瘤代谢的了解。