Role of Altered Nutrient Metabolism in Pancreatic Cancer

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and is the major form of pancreatic cancer. With an incidence on the rise, it currently ranks as the third leading cause of cancer death in the US. Despite recent advances in the understanding of its biology, genetics and risk factors, PDAC has maintained extremely poor prognosis, with a 5-year survival rate of only 10%. This mainly stems from its late diagnosis, aggressive nature and resistance to therapies. Thus, novel therapeutic approaches are urgently needed. Targeting altered metabolism in PDAC has been an area of extensive investigation for over a decade now. A major hurdle however, for most anti-tumor metabolic strategies, is the high risk of toxic side effects, given the essential roles of metabolic pathways in the maintenance of normal tissue homeostasis. This has indeed been the case for targeting polyamines in cancers. Polyamines are small, highly positively charged molecules involved in multiple fundamental processes of cell growth and survival, including the synthesis of nucleic acids, modifications of chromatin structure, gene transcription and mRNA translation. Polyamine levels are significantly increased in many cancers, including PDAC. Prior anti-tumor strategies focused on pharmacological inhibition of the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC1) with little success, partially due to risk of harming normal tissues at higher drug doses. This project identifies and aims at validating a dependency of pancreatic cancer, both in cultured cells in vitro and in mice in vivo, on an unconventional way for the synthesis of the polyamine precursor ornithine, specifically from glutamine via ornithine aminotransferase (OAT); this is compared to its synthesis in most adult normal tissues from arginine via arginase (ARG) activity. It also aims at identifying potential key players mediating the induction of this metabolic pathway by KRAS, the main oncogenic driver in PDAC, and to characterize the downstream effects of polyamines on transcriptional activation and gene expression in PDAC cells compared to normal pancreatic cells. The high dependency of PDAC, but not normal tissues on de novo ornithine synthesis from glutamine provides an attractive therapeutic window for treating pancreatic cancer patients with minimal toxicity.