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Reprogramming of immunosuppressive tumor microenvironment (TME) by targeting alternatively activated tumor associated macrophages (M2TAM), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Tregs), represents a promising strategy for developing novel cancer immunotherapy. Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite and mediator of chronic inflammation, has emerged as a powerful immunosuppressor in the TME through engagement with one or more of its 4 receptors (EP1-EP4). We have developed E7046, an orally bioavailable EP4-specific antagonist and show here that E7046 has specific and potent inhibitory activity on PGE2-mediated pro-tumor myeloid cell differentiation and activation. E7046 treatment reduced the growth or even rejected established tumors in vivo in a manner dependent on both myeloid and CD8+ T cells. Furthermore, co-administration of E7046 and E7777, an IL-2-diphtheria toxin fusion protein that preferentially kills Tregs, synergistically disrupted the myeloid and Treg immunosuppressive networks, resulting in effective and durable anti-tumor immune responses in mouse tumor models. In the TME, E7046 and E7777 markedly increased ratios of CD8+granzymeB+ cytotoxic T cells (CTLs)/live Tregs and of M1-like/M2TAM, and converted a chronic inflammation phenotype into acute inflammation, shown by substantial induction of STAT1/IRF-1 and IFNγ-controlled genes. Notably, E7046 also showed synergistic anti-tumor activity when combined with anti-CTLA-4 antibodies, which have been reported to diminish intratumoral Tregs. Our studies thus reveal a specific myeloid cell differentiation-modifying activity by EP4 blockade and a novel combination of E7046 and E7777 as a means to synergistically mitigate both myeloid and Treg-derived immunosuppression for cancer treatment in preclinical models.

E7046 is a potent and selective small molecule antagonist of the type 4 prostaglandin E2 (PGE2) receptor EP4. The discovery and evaluation of this novel EP4 antagonist for cancer treatment was recently presented at the AACR 2015 annual conference (abstract # 275). Here we show new evidence of E7046 in vivo activity against a series of syngeneic tumor models as well as its pharmacological effect on APCMin/+ mice, which possess a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene. We found that daily oral administration of E7046 was able to both slow down the growth of established subcutaneous tumors and significantly delay the recurrence of tumors after surgical resection. These activities of E7046 correlated with differences in the immune cell composition of the microenvironments of each type of tumor. In this context, cyclooxygenase 2 - positive (COX-2+) tumors that were rich in myeloid cells showed an enhanced response to E7046 regardless of their T lymphocyte infiltration status. In addition, E7046 was superior to the COX-2 inhibitor celecoxib against mutant APC-driven neoplastic polyp formation in the intestines of APCMin/+ mice exposed to dextran sodium sulfate. Using the APCMin/+ mouse model, we found that E7046 significantly reduced the combined colon polyp area and the size of individual polyps without influencing the total polyp number. For each of these parameters, E7046 activity against colon and small intestine tumors was greater than that of a comparable dose of celecoxib. Quantification of cyclin D1 staining in colon and small intestine polyps further indicated that both compounds led to a significant reduction in the proliferation of tumor cells, with a greater effect for E7046 compared to celecoxib. Overall, these preclinical results suggest that this agent should be further investigated in patients with COX-2+ tumors infiltrated with myeloid cells, including patients with APC-mutated colon cancer. First-In-Human study of E7046 is currently enrolling patients (IND 125272). Citation Format: Diana I. Albu, Jiayi Wu, Kuan-chung Huang, Renee Wright-Michaud, Shanqin Xu, Galina Kuznetsov, Xingfeng Bao, Mary Woodall-Jappe. Pharmacological profile of the PGE2 EP4 receptor antagonist E7046. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B198.