Novel PET imaging agents for understanding glutamine addiction in cancer

本建议书是为响应RFA-CA-11-005《高级活体成像》而编写的 了解癌症系统“。根据拟议的综合研究的需要，多项- PI项目将被用来最大限度地发挥“团队科学”在理解 癌症代谢的变化。Chosdosh和Kung实验室在 宾夕法尼亚大学将为先进的体内PET集成提供平台 成像技术与系统生物学方法，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 癌症患者肿瘤生长的诊断及其相关的肿瘤生物学研究 随着新型示踪剂在癌细胞中的摄取。结合正电子发射 体层摄影术(PET)这些新的探针可能会提供成像工具来研究重新编程 产生能量的代谢途径和维持肿瘤增殖的积木 细胞。由于与肿瘤新陈代谢和增殖相关的营养需求的变化，有 肿瘤特异性糖酵解增加和协调改变基因表达以维持 新陈代谢速度快。已证实主要肿瘤类型的糖酵解增加。 FDG-PET。然而，有相当一部分活动性肿瘤表现为阴性。 FDG摄取提示FDG阴性肿瘤可能使用其他来源的 能量和营养，如谷氨酰胺和其他氨基酸。最近的报告表明，有 是肿瘤细胞，如高表达c-myc基因的SF188细胞，这会导致 高水平的谷氨酰胺分解。基因表达的重新编程，上调 C-Myc、HER2/neu、Wnt、RAS、Akt等癌基因与能源转换 与建议的肿瘤谷氨酰胺分解和FDG-PET相关的探针将被评估。 我们将开发一系列18F标记谷氨酸的制备方法并对其进行特定的微调 癌基因在转基因小鼠中的表达。谷氨酸将在肿瘤细胞中进行测试，如 AS 9L、C6、PC3和SF188细胞，表现出对较高氨基酸的倾向 摄取和谷氨酰胺分解。此外，肿瘤细胞的摄取将与癌基因相关。 通过使用c-myc，HER2/neu， WNT1、RAS和Akt在乳腺癌中过表达。成功的谷氨酰胺显像剂将是 选择对转基因小鼠进行PET成像的肿瘤，在其中代谢变化显示 倾向于使用谷氨酰胺衍生物作为主要的营养来源。建议的18F 标记谷氨酰胺可作为探测谷氨酰胺成瘾肿瘤的新代谢标志物 FDG-PET未检测到。代谢性生物标志物的研究进展 为推进肿瘤的诊断和治疗提供了令人振奋的机会。这部小说 肿瘤代谢显像剂可能为评价肿瘤的代谢状态提供新的方法 肿瘤在人类癌症中的生长，促进了我们对肿瘤的理解 PET显像检测癌基因表达与肿瘤代谢的关系

This proposal is written in response to a RFA-CA-11-005 "Advanced In Vivo Imaging to Understand Cancer Systems". 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.