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Research Proposal

This proposal seeks to translate new insights concerning oncogene-induced changes in nutrient metabolism into the improved diagnosis and treatment of pancreatic cancer. Mammalian cells fuel their growth and proliferation through the metabolism of two main bioenergetic substrates, glucose and glutamine. Mammalian cells normally require growth factor signaling to direct sufficient glucose and glutamine uptake to maintain survival. Investigations of PI3K and its downstream effector, Akt, have demonstrated that these oncogenes play a direct role in stimulating glucose uptake and in orchestrating the metabolic conversion of transformed cells to aerobic glycolysis, the so-called Warburg effect. Constitutive PI3K/Akt pathway activation correlates clinically with the ability to image tumors using 18-fluoro-2-deoxyglucose by positron emission tomography (FDG-PET). Inhibition of FDG uptake by tumors has been used as a robust indicator of the therapeutic response to alkylating drugs and/or targeted therapies in many different tumor types. A notable exception to the FDG-PET paradigm is pancreatic cancer.

In contrast to most other major tumor types, global genomic analysis of pancreatic tumors has revealed a relative paucity of mutations targeting the PI3K pathway. Therapies such as alkylating drug treatment, which effectively induce cell death in glucose-addicted cells, have proven ineffective in pancreatic cancer. Pancreatic cells depend on glutamine for their survival in vitro, even when cultured in abundant glucose. Recently, this Dream Team’s (DT) Principal Investigators established that Myc transformation stimulates a cell’s conversion to a glutamine-dependent metabolism. Specifically, Myc regulates a transcriptional program that activates genes governing mitochondrial glutaminolysis, resulting in glutamine addiction.

Correspondingly, global genomic analysis of pancreatic tumors has documented a high frequency of mutation in the Wnt/β-catenin pathway and in the K-ras oncogene. These mutations are known to converge on Myc expression and protein stability.

Although the glutamine dependence of pancreatic cell lines has been established, there are no clinical methods to evaluate the use of glutamine by tumors in vivo. This proposal seeks to address whether some or all pancreatic cancers depend on glutamine in vivo, and whether this dependence can be exploited in the clinic. Our team of tumor biology and imaging experts will focus on the development of clinically useful PET imaging agents for quantification of glutamine uptake and metabolism in vivo. Both 11C- and 18F-substituted forms of glutamine will be developed and used as imaging agents, first in animal models of pancreatic adenocarcinoma and in human pancreatic cancer xenografts, and finally in the preoperative evaluation of patients with pancreatic carcinoma. The data from these imaging studies will be correlated with the metabolomic profile and genotype of the tumor as isolated at surgery.

In a complementary set of aims, our DT seeks to determine whether agents that impair the ability of cells to utilize glutamine as a bioenergetic substrate can be developed for the treatment of pancreatic cancer. Although previous attempts to exploit the glutamine addiction of pancreatic carcinoma have failed because of toxicity, studies of myc-directed glutaminolysis have identified novel intracellular targets that may avoid the systemic toxicities of prior therapies. These include therapeutic suppression of glutamate-dependent transamination using aminooxyacetate, inhibition of the mitochondrial dependent steps of glutaminolysis with the Type 2-diabetic agent, phenformin, or the suppression of lactate production, the secreted end product of both glutaminolysis and aerobic glycolysis, using recently developed LDH-A inhibitors. The tumor selectivity of these interventions in pancreatic carcinoma is predicted to be enhanced by loss of the tumor suppressors p53 and/or p16INK4a and thus efficacy of the treatments may correlate with tumor genotype.Each of these therapies will be examined initially in preclinical animal models and human pancreatic cancer xenografts.Treatments that prove efficacious in these preclinical models will then be utilized in Phase I/II clinical trials and the results correlated with FDG, 18F-1-thymidine (FLT), and 18F-glutamine (FGlu) imaging, tumor metabolomic profile, and tumor genotype.