Novel PET imaging agents for understanding glutamine addiction in cancer

本提案是为了响应RFA-CA-11-005“高级体内成像， 了解癌症系统”。根据需求提出了综合研究的多层次、多层次的 PI项目将用于最大限度地发挥“团队科学”的潜力， 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，以了解癌症的体内成像。 本项目的目的是制备和评价18F标记的谷氨酰胺衍生物， 诊断癌症患者的肿瘤生长，并研究与肿瘤生长相关的癌症生物学。 与癌细胞中新示踪剂的摄取有关。结合正电子发射 断层扫描（PET），这些新的探头可以提供成像工具，研究重新编程的 用于产生能量和构件以维持肿瘤增殖的代谢途径 细胞由于与肿瘤代谢和增殖相关的营养需求不断变化， 糖酵解的肿瘤特异性增加和协调改变基因表达，以维持糖酵解。 高代谢率。糖酵解在主要肿瘤类型中的增加已经被证明 FDG-PET然而，有相当一部分活动性肿瘤显示阴性， FDG摄取表明FDG阴性肿瘤可能使用替代来源的 能量和营养，如谷氨酰胺和其他氨基酸。最近的报告显示， 是肿瘤细胞，例如显示高c-myc基因表达的SF 188细胞，其导致肿瘤细胞的凋亡。 高水平的去乙酰氨基酶解。基因表达的重编程， 癌基因，如c-Myc、HER 2/neu、Wnt、Ras和Akt，以及能量来源的转移 将评估与肿瘤去甲氨溶解和FDG-PET的拟议探针的相关性。 我们将开发制备一系列18F标记的谷氨酰胺的方法，并对18F标记的谷氨酰胺进行特异性微调。 转基因小鼠中癌基因的表达。谷氨酰胺将在肿瘤细胞中进行测试， 如9 L、C6、PC 3和SF 188细胞，这些细胞已证明具有更高氨基酸的倾向， 摄取和氨解。此外，肿瘤细胞的摄取将与癌基因 通过使用c-MYC，HER 2/neu， Wnt 1、Ras和Akt过表达的乳腺癌。成功的谷氨酰胺显像剂将是 选择用于PET成像的转基因小鼠肿瘤，其中代谢变化显示 优选使用谷氨酰胺衍生物作为主要营养源。建议18F 标记的谷氨酰胺可作为探测谷氨酰胺成瘾性肿瘤的新代谢标记物 FDG-PET未检测到。拟议的替代代谢生物标志物的发展 为肿瘤的诊断和治疗提供了一个令人兴奋的机会。小说 肿瘤代谢显像剂可能会导致新的方法来评估代谢状态， 肿瘤在人类癌症中的生长，并提供我们对肿瘤的理解 癌基因表达和肿瘤代谢的PET成像。

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.