Abstract 2845: Prostaglandin E receptor EP4 antagonist RQ00015986 inhibits breast cancer metastasis and protects natural killer cells from PGE-mediated immune suppression

Abstract

Abstract The cyclooxygenase-2 (COX-2) pathway is upregulated in breast and other malignancies. The COX-2 product prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on a family of G-protein-coupled receptors (EP1-EP4). In breast and colon malignancies, EP4 is a principle mediator of pro-tumorigenic and pro-metastatic activities. Our previous studies demonstrated that targeting EP4 with shRNA or by pharmacologic antagonists of EP4 leads to reduced metastasis in a preclinical model of metastatic breast cancer. These studies and others establish EP4 as a potential therapeutic target, however, there is a paucity of effective EP4 antagonists available for preclinical and clinical investigation. Using a novel orally available EP4 selective antagonist, RQ00015986, we have evaluated efficacy in a syngeneic murine model of metastatic breast cancer. Murine and human breast cancer cells express EP4 and receptor occupation with PGE2 (binds all EP) or with PGE1-OH (EP4 agonist) results in adenyl cyclase activation and elevated intracellular cAMP. RQ00015986, in uM/L concentrations, was able to prevent EP4-mediated adenyl cyclase activation in murine mammary tumor cell lines 66.1 and 410.4. Breast tumor cells migrate in response to either PGE2 or PGE1-OH and RQ00015986 inhibited this response. Pretreatment of 66.1 cells with RQ00015986 prior to i.v. injection into syngeneic mice resulted in 58-69% inhibition in numbers of lung tumor colonies. Natural Killer (NK) cells are critical to the control of metastatic dissemination. The ability of RQ00015986 to inhibit lung tumor colonization was completely lost in hosts depleted of mature NK cells. We have reported previously that NK cell functions in tumor-bearing mice are severely depressed through the actions of tumor-derived PGE2 acting on EP4 receptors expressed on the NK cell. The capacities of NK cells to migrate, to produce cytokines and to lyse mammary tumor target cells are each inhibited through PGE2. In the presence of RQ00015986, the capacity of cultured NK cells to migrate and to produce Interferon-α was restored to normal levels. More interestingly, treatment of tumor-bearing mice with RQ00015986 in vivo also restored NK cell functions. This report provides evidence that a novel EP4 antagonist may have therapeutic potential in cancer and may act by antagonizing EP4 prometastatic functions on the malignant cell as well as protecting NK effector cells from PGE2-mediated immune suppression. 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 2845. doi:1538-7445.AM2012-2845