Abstract 116: Targeting glutamine addiction in pancreatic cancer
Authors: Yang Xiaoyu , Muñoz Amanda R. , Huang Shih-Bo , Hanes Martha , Bedolla Roble G. , Chakravarthy Divya , Su Angel , Mulamreddy Varsha , Kovalskyy Dmytro , Rivas Paul , Michalek Joel , Ghosh Rita , Kumar Addanki P 
Published: August 2019

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with appallingly poor outcome. Recent years have witnessed the development of a number of combination therapies that have produced modest survival improvement but at the cost of increased adverse effects. A phenomenon that contributes to the dismal prognosis and therapeutic resistance is a unique characteristic of PDAC called desmoplasia. Desmoplasia is initiated by activation of pancreatic stellate cells (PSCs), which through excessive deposition of extracellular matrix components, leads to expansion of tumor stroma that hinders drug penetration. We have recently shown that glutamine mediates communication between PSCs and pancreatic cancer cells (PCCs). Remarkably, a small molecule inhibitor palmatine (PMT) suppresses glutamine-induced PSC-PCC communication and potentiates gemcitabine (GEM) activity in part through downregulation of survivin. Survivin expression is correlated not only with unfavorable overall survival but also therapeutic resistance. In this study we therefore examined the mechanism associated with glutamine-mediated PSC-PCC interaction. We also designed experiments to test the hypothesis that PMT inhibits survivin to disrupt these interactions to potentiate anti-proliferative activity of GEM. Our results indicate that PMT not only interacts with pTyr p705 binding site in the SH2 domain of STAT3 (canonical), but also interacts at the interface of DNA and the linker domain (non-canonical). PMT-STAT3 interaction resulted in decreased phosphorylation with no significant effect on total levels of STAT3 in pancreatic cancer cells following treatment with PMT. Furthermore, PMT treatment attenuated (i) glutamine-mediated increased levels of pSTAT3 and its downstream target survivin; (ii) glutamine-mediated increased survivin reporter activity and (iii) glutamine-mediated enhanced proliferation and clonogenicity in multiple cell lines. Collectively, these data suggest that PMT abrogates glutamine-induced biological outcome through reduced STAT3/survivin signaling. We further tested the preclinical efficacy of PMT in combination with GEM using the syngeneic orthotopic KPC mouse model. Our results show significantly decreased mean log 10 tumor weight in response to treatment with PMT plus GEM (0.08±1.13) relative to controls (1.87±0.21) or single agent treatment (1.48+0.67; p&lt;0.001). Cox regression analysis indicated risk of death decreases with intervention (p&lt;0.001). Taken together, these data show potential clinical utility for the combination of PMT plus GEM in the treatment of pancreatic cancer. Supported by VA-Merit Award I01 BX 003876 (APK).

Citation Format: Xiaoyu Yang, Amanda R. Muñoz, Shih-Bo Huang, Martha Hanes, Roble G. Bedolla, Divya Chakravarthy, Angel Su, Varsha Mulamreddy, Dmytro Kovalskyy, Paul Rivas, Joel Michalek, Rita Ghosh, Addanki P Kumar. Targeting glutamine addiction in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 116.