Pancreatic ductal adenocarcinoma is dependent on an unconventional pathway for polyamine synthesis.

Abstract Targeting altered metabolism in pancreatic ductal adenocarcinoma (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 for toxicity, given the essential roles of metabolic pathways in the maintenance of normal tissue homeostasis. Indeed, this has 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. In this project, using both in vitro and in vivo mouse models of PDAC, we identified a dependency of PDAC on an unconventional way for the synthesis of the polyamine precursor ornithine, specifically from glutamine via ornithine aminotransferase (OAT); this is in contrast to its synthesis in most adult normal tissues from arginine via arginase (ARG) activity. We also identified potential key players mediating the induction of this metabolic pathway via KRAS, the main oncogenic driver in PDAC and are currently characterizing the downstream effects of polyamines on pancreatic tumor cells. The high dependency of PDAC, compared to normal tissue, on de novo ornithine synthesis via OAT provides an attractive therapeutic window for treating pancreatic cancer patients with minimal toxicity. Citation Format: Min-Sik Lee, Insia Naqvi, Courtney Dennis, Lucas Dailey, Alireza Lorzadeh, Tamara Zaytouni, Ashley Adler, Daniel S. Hitchcock, Lin Lin, Unmesh Jadhav, Clary B. Clish, Nada Y. Kalaany. Pancreatic ductal adenocarcinoma is dependent on an unconventional pathway for polyamine synthesis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-028.