Abstract A90: Non-canonical effects of PTEN restoration therapy contribute to improved survival in a GEM model of pancreatic ductal adenocarcinoma

Abstract

Expression of the PTEN tumor suppressor protein is frequently altered in human pancreatic tumors, and deletion of PTEN in genetically engineered mouse (GEM) models accelerates pancreatic tumorigenesis. However, efforts to target components of the PTEN pathway, through inhibitors of PI3-Kinases, AKT, or mTOR, have failed to provide significant survival benefit to date. We utilized a naturally occurring, membrane-permeable variant of the PTEN protein, called PTEN-Long, to restore PTEN-function in trans to established pancreatic tumors in the KPC GEM model of pancreatic ductal adenocarcinoma (PDA). Combination PTEN-Long + gemcitabine therapy prolonged overall survival by 2-fold in this model and led to frank regressions of varying duration in a subset of tumors. In order to study the mechanisms of response to PTEN-Long therapy, we utilized variants of the PTEN-Long protein that are functionally mutated in different ways. A phosphatase-dead variant of PTEN-Long failed to have any effect on tumor growth in KPC mice. Interestingly, a variant of PTEN-Long that is no longer membrane permeable actually reduced overall survival in combination with gemcitabine, perhaps indicating a role for the protein in the extracellular matrix. Finally, we compared the effect of PTEN-Long in KPC mice to that of the pan-PI3K inhibitor GDC-0449. In contrast to PTEN-Long + gemcitabine, GDC-0449 + gemcitabine failed to extend survival or produce tumor regressions. Investigating the distinctions between pan-PI3K inhibition and PTEN restoration, we noted disparate, indeed opposite, effects of these two therapies on blood glucose maintenance and insulin levels, strongly that PTEN can function though additional, non-canonical intermediates beyond phospho-inositides. With the development of a clinical grade PTEN-Long material under way, we believe that these studies highlight the potential therapeutic utility of PTEN restoration therapy in PDA. These experiments provide the opportunity to dissect non-canonical aspects of PTEN signalling through in vivo structure/function analysis in GEM models of pancreatic cancer. Citation Format: Benjamin Hopkins, Carmine Palermo, Roshan A. Ahmed, Stephen A. Sastra, Ramon Parsons, Kenneth P. Olive. Non-canonical effects of PTEN restoration therapy contribute to improved survival in a GEM model of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A90.