Abstract 3472: Dual PI3K/mTOR inhibition in PIK3CA mutant pancreatic cancers

Abstract

Abstract Background: Pancreatic cancer is one of the most deadly cancer diagnoses with limited long-term survival for patients, even with early-stage disease. 3-5% of these cancers have mutations in the phosphoinositide 3-kinase (PI3K) signaling pathway. There is growing interest in targeting cancers with this mutation using specific pathway inhibitors. We have previously proven that dual PI3K/mTOR inhibition is sufficient to decrease tumor growth in mice with a PI3K p110* transgene. Here we aim to determine if this treatment can induce a response in pancreatic cancers with the human PIK3CA H1047R hotspot mutation. Methods: Transgenic mice were developed using a cre lox-p system (Pdx1-cre) to develop PIK3CA H1047R (PCPK mice) pancreatic adenocarcinomas. Tumors were harvested and grown in spheroid culture. These were treated with increasing concentrations of BEZ235, a dual PI3K/mTOR inhibitor. Treatment groups were compared using spheroid diameter changes and metabolic activity via NADH and FAD+ quantitation. Additionally, immunofluorescence staining was performed and quantified on treated spheroid cultures. PET/CT diagnostics were performed and analyzed pre- and post- treatment with BEZ-235 on a cohort of these experimental mice. Treated tissues were resected for immunohistochemistry and Western blot analyses. Results: Organotypic PCPK spheroid cultures were treated with BEZ235 in the culture media for 48 hours. Pre- and post-brightfield imaging demonstrated a modest reduction in the percent change in spheroid diameter compared to control (control: 41.8%, BEZ235 100nM: 9%, BEZ235 200nM: -7.7%, BEZ235 400nM: -14.3%; p<0.001). This stability of the spheroid size correlated with minimal differences between the control and treated spheroids using the optical metabolic imaging, including nonsignificant changes in NADH lifetime, FAD+ lifetime and the optical redox ratio (p=NS). PCPK mice (n=10) aged until they developed cancers and then were treated with BEZ235 for 14 days. Pre- and post-positron emission tomography/computed tomography (PET/CT) were performed. Nonsignificant changes in tumor volume and PET avidity were seen between the treatment groups. Both in vitro and in vivo treatments with BEZ235 proved to have no significant change in tumor avidity in this model. Immunoblotting demonstrated persistent activation of the PI3K pathway despite BEZ235 treatment in these spheres and mice as measured by persistent phosphorylation of RPS6 and 4EBP1. Conclusions: Despite significant responses being previously detected in mice with pancreatic tumors initiated by the PI3K p110* transgene, BEZ235 did not result in a similar treatment effect in PCPK mice possessing the human PIK3CA H1047R hotspot mutation. Further studies will examine the potential resistance mechanisms of these tumors to this therapy and potential ways in which to overcome this resistance. Citation Format: Susan Payne, Mitchell Depke, Alex Yueh, Joseph T. Sharick, Peter F. Favreau, Cheri A. Pasch, Linda Clipson, Kristina A. Matkowskyj, Melissa Skala, Dustin A. Deming. Dual PI3K/mTOR inhibition in PIK3CA mutant pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3472.