Abstract 117: Pharmacological targeting of activated PSC decreases resistance to gemcitabine and increases survival in murine PDA

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of cancer owing to its insensitivity to many chemotherapeutic drugs. Gemcitabine remains a cornerstone of PDA treatment despite suboptimal efficacy in clinics. One major mechanism by which PDA becomes resistant to gemcitabine is its conversion to inactive derivative, dFdU by upregulation of the enzyme, cytidine deaminase (Cda) in cancer cells. Activated pancreatic stellate cells (PSC) are the major source of IGF1 in the tumor microenvironment, which may be responsible for an increase in Cda expression in cancer cells. We previously reported a rationally designed protein, ProAgio that targets integrin αVβ3 at a novel site. Here we demonstrate that ProAgio specifically induces apoptosis of integrin αVβ3-expressing activated PSC and therefore circumvents gemcitabine resistance in murine PDA models. Objective: To test whether targeting activated PSC restores chemotherapeutic sensitivity in previously unresponsive PDA tumors in a murine model. Methods: To study the effect of ProAgio and gemcitabine combination in PDA, we used two murine PDA models: a) KP orthotopic mouse model where KPC cells were orthotopically injected into the pancreas and, b) LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model. Mice were treated with 20 doses of ProAgio (10mg/kg; i.p.) and 10 doses of gemcitabine twice weekly (50mg/kg; i.p.). IGF1 and Cda levels were analyzed by ELISA and immunohistochemistry. The intratumoral levels of the gemcitabine prodrug 2′,2′-difluorodeoxcytidine (dFdC) and the inactivated and activated metabolites (2′,2′-difluorodeoxyuridine (dFdU) and gemcitabine triphosphate (dFdCTP) respectively were determined by LCMS. Results: Our data in murine PDA models clearly demonstrate that pharmacological targeting of activated PSC by ProAgio can stabilize PDA, and when combined with gemcitabine significantly increased the survival benefit by 3-fold (p<0.001). Pharmacological targeting of activated PSC by ProAgio consequently decreases IGF1R signaling in cancer cells. As a result, there is a decrease in Cda expression leading to an increase in active metabolite, dfdCTP in the tumor, which contributes to the enhanced efficacy of gemcitabine. In conclusion, our findings for the first time demonstrate the mechanistic approach to target activated PSC, resulting in decreased Cda expression and enhanced gemcitabine delivery, thereby restoring chemotherapeutic sensitivity in murine PDA models. Citation Format: Ravi Chakra Turaga, Malvika Sharma, Falguni Mishra, Zhi-Ren Liu. Pharmacological targeting of activated PSC decreases resistance to gemcitabine and increases survival in murine PDA [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 117.