Sustained Polyamine Depletion for the Treatment of Pancreatic Ductal Adenocarcinoma

Abstract

Of all human tissues, the human pancreas has the highest level of the polyamine spermidine. Pancreatic cancers use these high levels to drive their growth. Indeed, polyamine metabolism plays critical roles in many cellular processes including transcription, translation, and chromatin remodeling. Therefore, therapies, which deplete the intracellular pools of the native polyamines putrescine, spermidine, and spermine, result in cell growth arrest. Inhibitors have been designed to inhibit the rate limiting enzyme in polyamine biosynthesis, i.e., ornithine decarboxylase (ODC). Indeed, the ODC inhibitor difluoromethylornithine (DFMO), has a forty year history in the clinic with mixed results as an oncology therapeutic. Unfortunately, DFMO‐treated cancer cells often respond by increasing polyamine import to restore their depleted polyamine pools. Therefore, in order to establish sustained intracellular polyamine depletion, a combination therapy of DFMO and a polyamine transport inhibitor (PTI) is required.New polyamine transport inhibitors are needed because all existing PTIs are polyamine‐based and can give rise to off‐target effects. To address this need, we have developed new PTI agents predicated upon a benzoic acid scaffold. This report describes our development of these new agents and their use to inhibit the uptake of radiolabeled spermidine and block the rescue of DFMO‐treated pancreatic cancer cells by exogenous spermidine. Since pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic cancer, we have focused on this cancer type in our studies. A success here could lead to new therapies for the world's most deadly cancer, which currently has a five year survival of only 8%.Support or Funding Information2016 Florida Translational Research Program and the 2018 Bankhead‐Coley Cancer Research Program Award # 8BC05.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.