Abstract 893: Anticancer effect and mechanism of prostaglandin E2 receptor EP4 antagonist

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Molecular studies reveal that over-expression of cyclooxygenase-2 (COX-2) is a prominent feature of premalignant and malignant neoplasms. The increased COX-2-mediated prostaglandin-E2 (PGE2) production has a strong association with various cancers, by promoting cell survival, cell growth, migration, invasion, angiogenesis, and immunotolerance. The use of COX-2 selective inhibitors has shown promise in the prevention and treatment of various cancers, however, the chronic use of COX-2 inhibitors is associated with an increased risk of cardiovascular adverse effects. Therefore, there is an urgent need to further understanding of the downstream mechanisms by which PGE2 promotes tumorigenesis and more effective strategies for the treatment of cancer. There are four PGE2 receptors, i.e., EP1, EP2, EP3, and EP4, involved in the pharmacology of PGE2. Accumulating evidences suggest that EP4 is the responsible receptor for PGE2 / COX-2-mediated tumorigenic signals in cancer cells and cancer microenvironment. On the other hands, signals from other prostaglandin receptors, e.g. IP and EP1, are reported to inhibit cancer proliferation or metastasis. These evidences suggest that selective blockade of EP4 would offer anti-cancer efficacy and safety advantages over COX-2 inhibition as cancer therapy. We have developed novel plural EP4 antagonists, with pA2 values of nanomolar range which are selective against other EP receptors. EP4 antagonists inhibited the PGE2-dependent productions of key molecules for cancer promotion i.e. VEGF, IL-23, and IL-6 in macrophages, dendritic cells, and PBMC, respectively. At the same time EP4 antagonist reversed PGE2 -induced TNFα and IL-12 suppression in human whole blood. As a consequence, EP4 antagonists exhibited anti-cancer activity in lung, GI, and prostate cancer models. These results indicate that selective EP4 antagonists show anti-cancer effect mediated by multifaceted mechanisms, and represent an attractive medicine for anti-cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 893. doi:1538-7445.AM2012-893