Abstract 3139: Disrupting prostaglandin E2 signaling to reverse treatment resistance in cancer
Authors: Markosyan Nune , Quinones Liz , Aurora Charu , Joshi Nikhil , Kim Ilkyu , Stanger Ben Z. , Vonderheide Robert H. 
Published: June 2022

Abstract
Pancreatic adenocarcinoma (PDA) accounts for 3% of all cancers in the USA and 7% of all cancer deaths partly because of its resistance to immunotherapy. PDA manifests itself as a desmoplastic, myeloid cell-rich tumor with a notable paucity of T cells. Pathway analysis of the T cell low, immunotherapy resistant mouse PDA cell lines has identified the prostaglandin E2 (PGE2) synthetic pathway as one of the most upregulated ones. We have previously shown that the deletion or pharmacological inhibition of COX-2, the rate-limiting PGE2 synthesis enzyme, slows the tumor growth and synergizes with immunotherapy to further suppress PDA progression. The current study investigates how the disruption of PGE2 signaling through its receptors, EP4 and EP2, can affect PDA. We use EP receptor genetic and pharmacological inhibition models - we disrupt EP signaling on tumor cells only or systemically, test the effects in T cell low, intermediate, and high PDA tumors, alone or in combination with chemo and immunotherapy. EP4 receptor blocker combined with the agonistic CD40 and anti-PD-1 antibodies significantly increased tumor-free survival of the T cell intermediate PDA implanted tumor-bearing (TB) mice (57% tumor-free in treated vs 0% in the control group). The same combination therapy tended to increase the survival in autochthonous tumor-bearing KrasG12D and p53R172H transgenic mice (p=0.08). CRISPR knockout (KO) of the EP4 in the T cell low cell line abolished the growth of subcutaneous (SQ) tumors and significantly slowed the progression of orthotopically implanted tumors (p=0.009 EP4 KO vs control). Treatment of the SQ T cell low TB mice with EP2/EP4 blockers in combination with either anti-PD-1 or chemotherapy slowed the tumor growth compared to the controls (p=0.002 and p=0.004, respectively) and increased the survival (p=0.007 and p=0.002, respectively). A week of combination treatment resulted in changes in the myeloid cell compartment of the TME - an increase in the proportion of M1 macrophages and type 1 conventional dendritic cells with no significant changes in the T cell compartment. The study demonstrates an alternative approach to targeting the PGE2 pathway in tumors and aims to develop a multiprong treatment regimen to reverse the therapy resistance in PDA. Normal 0 false false false EN-US X-NONE X-NONE/* Style Definitions */table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} &lt;![endif]–&gt;
Citation Format: Nune Markosyan, Liz Quinones, Charu Aurora, Nikhil Joshi, Ilkyu Kim, Ben Z. Stanger, Robert H. Vonderheide. Disrupting prostaglandin E2 signaling to reverse treatment resistance in 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 3139.