Abstract 1064: Targeting stromal autotaxin synergizes with TGF beta inhibition in pancreatic cancer

Abstract

Abstract The TGFβ receptor inhibitor galunisertib (GAL) has been demonstrated as an effective strategy for the treatment of pancreatic cancer (PC) patients, in part through the modulation of stromal microenvironment. However, alternative pathways driving stromal paracrine signals might impair its effect. Autotaxin (ATX) is an enzyme that converts lysophosphatidylcholine into its bioactive lipid, lysophosphatidic acid (LPA), which in turn promotes inflammation and fibrosis, and contributes to treatment resistance. IOA-289 is a novel ATX inhibitor in clinical development for the treatment of tumors burdened with a high degree of stromal involvement. Here, we hypothesized that ATX could sustain an adaptive response upon inhibition of TGFβ receptor signaling, impairing GAL antitumor activity.Among ten different murine PC orthotopic models, mice bearing RC416 tumors had the highest plasma levels of TGFβ1 as well as high infiltration of cancer associated fibroblasts (CAFs) and fibrosis as measured by Masson’s staining. In coculture models of RC416 with murine pancreatic stellate cells (mPSC4), we measured a significant overexpression of ATX upon treatment with galunisertib mainly by mPSC4, which showed a skewing toward an inflammatory iCAF phenotype through the upregulation of CXCL1 and LY6C1 and the down-regulation of myCAF markers including ACTA2 and Taglin. In the RC416-mPSC4 coculture model, anti-tumor activity was achieved with a combination of gemcitabine plus GAL plus IOA-289, whereas these treatments were ineffective in single culture conditions. Mice bearing RC416 tumors reached a statistically significantly longer survival following treatment with gemcitabine plus IOA-289 or gemcitabine plus GAL [median overall survival (mOS)= 35 days, p<0.05] compared with any single treatment or no treatment control. Most importantly, mice treated with the triple combination of gemcitabine plus IOA-289 and galunisertib had a significantly longer survival than any double combination treatments [mOS=47 days, p<0.05]. In mice treated with gemcitabine in combination with IOA-289 and/or GAL we measured a significantly reduced infiltration of CAFs, a reduction in plasma levels of CTGF and a diminished degree of fibrosis compared with any single control treatment.In conclusion, we demonstrate that the overexpression of autotaxin by stromal PSC might be an adaptive mechanism in response to TGFβ receptor inhibition. IOA-289 is a novel agent that warrants further clinical development in combination with gemcitabine plus GAL for the treatment of PC patients. Citation Format: Fabio Sabbadini, Monica Bertolini, Domenico Mangiameli, Serena Contarelli, Zoë Johnson, Michael M. Lahn, Silvia Pietrobono, Davide Melisi. Targeting stromal autotaxin synergizes with TGF beta inhibition in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1064.