Abstract 1179: EP4 receptor antagonism in paclitaxel-resistant ovarian clear cell carcinomas that overexpress class III β-tubulin

Abstract

Abstract OBJECTIVES: Advanced ovarian clear cell carcinoma (OCCC) is associated with a survival disadvantage relative to ovarian serous carcinoma following platinum/taxane-based chemotherapy and optimal cytoreduction. Prostaglandin E2 (PGE2) contributes to disease progression through modulation of several G-protein coupled receptors (EP1-4) [Fig.1a]. The addition of upstream COX inhibition to platinum/taxane-based chemotherapy in the first-line phase II setting in ovarian cancer has been disappointing,a possibly due to compensatory upregulation of COX isoenzymes and negation of protective effects of EP1. Selective antagonism of EP4 may therefore pose a more rational strategy than global COX inhibition. Paclitaxel administration has been shown to upregulate components of the COX pathway.b Class III β-tubulin is a marker for paclitaxel resistance and is widely overexpressed in OCCC. The purpose of this study is to demonstrate that EP4 inhibition may overcome paclitaxel resistance in OCCC that overexpress class III β-tubulin. METHODS: Expression of EP4 receptor and class III β-tubulin was quantified using immunohistochemistry and Western blot in solid tissues and cell lines. Standard metabolic growth and migration assays were employed to test the effects of drug treatment (paclitaxel and EP4 inhibitors RQ-15986/AH-23848) with and without EP4 silencing using siRNA. RESULTS: OCCC overexpress class III β-tubulin/EP4 relative to normal ovary [Fig. 1b/c]. EP4 staining intensity was 2+ in 100% OCCC using an ovarian cancer tissue microarray (62 cores, 13% OCCC); this rate was only 26-56% among other histologies. EP4 inhibition reduces growth of paclitaxel-resistant cells [Fig. 1d]. Likewise, treatment with EP inhibitors [Fig.1 e-top] and silencing of EP4 resulted in reduced migration [Fig.1 e-bottom]. CONCLUSIONS: Selective antagonism of PGE2 through EP4 receptor inhibition may represent a powerful targeted therapy for paclitaxel-resistant OCCC. Further study including simultaneous treatment (EP4 inhibitor+paclitaxel) and larger samples sizes is required. REFERENCES: a Reyners et al. A randomized phase II study investigating the addition of the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin as first-line chemotherapy for stage IC to IV epithelial ovarian cancer, fallopian tube or primary peritoneal carcinomas: the DoCaCel study. Ann Oncol 2012; 23:2986-902. b Moos et al. Effects of taxol/taxotere on gene expression in macrophages: induction of the PGH synthetase-2 isoenzyme. J Immunol 1999;162:476-73. Citation Format: Dana M. Roque, Danielle Meir-Levi, Gautam G. Rao, Paul Staats, Amy Fulton, Jocelyn Reader. EP4 receptor antagonism in paclitaxel-resistant ovarian clear cell carcinomas that overexpress class III β-tubulin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1179. doi:10.1158/1538-7445.AM2017-1179