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.

Public Health Relevance

We propose to prepare and evaluate 18F labeled glutamines for mapping modifications of metabolic pathways in tumor due to changing nutrient needs for metabolism and proliferation. Reprogramming of genetic expression, such as oncogenes - c-Myc, HER2/neu, Wnt, Ras and Akt, on shifting the energy source for tumor growth will be studied. The new alternative metabolic biomarkers for probing tumor metabolism may lead to development of selective anti- tumor agents for diagnosis and explore the relationship of gene expression for tumor metabolism associated with changes of nutritional needs in tumor proliferation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZCA1-SRLB-9 (O1))
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Menkens, Anne E
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University of Pennsylvania
Schools of Medicine
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Dunphy, Mark P S; Harding, James J; Venneti, Sriram et al. (2018) In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine. Radiology 287:667-675
Zhu, Lin; Ploessl, Karl; Zhou, Rong et al. (2017) Metabolic Imaging of Glutamine in Cancer. J Nucl Med 58:533-537
Zhou, Rong; Pantel, Austin R; Li, Shihong et al. (2017) [18F](2S,4R)4-Fluoroglutamine PET Detects Glutamine Pool Size Changes in Triple-Negative Breast Cancer in Response to Glutaminase Inhibition. Cancer Res 77:1476-1484
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