Tempest Therapeutics, Brisbane, California.
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
Cancer Res Commun. 2023 Aug 8;3(8):1486-1500. doi: 10.1158/2767-9764.CRC-23-0249. eCollection 2023 Aug.
While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8 T cells as compared with single EP antagonists. CD8 T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC) spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist.
Prostaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule.
目的：虽然前列腺素 E2（PGE2）在促进恶性进展中的作用已得到充分证实，但如何最佳阻断 PGE2 信号通路仍有待证明。针对前列腺素途径的临床试验靶向药物已显示出活性，但由于没有足够的意义或剂量限制毒性，这些药物未能获得批准。PGE2 通过四个受体（EP1-4）传递信号来调节肿瘤进展。EP2 和 EP4 信号通过增强 cAMP 的产生来加剧肿瘤病理并具有免疫抑制作用。EP1 和 EP3 信号通过增加 IP3 和减少 cAMP 产生相反的作用。本研究使用可用的单个 EP 受体的小分子拮抗剂、环氧化酶-2（COX-2）抑制剂塞来昔布或新型双重 EP2/EP4 拮抗剂，测试了哪种方法阻断 PGE2 信号能最佳恢复小鼠和人免疫细胞的免疫活性，并在同源、自发性和异种移植肿瘤模型中恢复抗肿瘤活性。
方法：我们发现，与单个 EP 拮抗剂相比，EP2 和 EP4 的双重拮抗作用显著增强了 PGE2 抑制的小鼠和人单核细胞和 CD8 T 细胞的激活。单个 EP1 和 EP3 拮抗剂抑制 CD8 T 细胞的激活。与塞来昔布相比，双重 EP2/EP4 PGE2 受体拮抗剂增加了肿瘤微环境中淋巴细胞的浸润，并显著降低了多种肿瘤模型中的疾病负担，包括 APC 自发性结直肠肿瘤模型。
结果：这些结果支持这样一种假说，即 EP2 和 EP4 受体信号的冗余需要一种双重阻断 EP2 和 EP4 的治疗策略。本研究描述了 TPST-1495，一种首创的口服小分子双重 EP2/EP4 拮抗剂。
结论：前列腺素（PGE2）驱动肿瘤进展，但该途径尚未得到有效治疗。我们通过阻断 EP2 和 EP4 PGE2 受体信号以及使用单个分子，证明了显著增强的免疫效力和抗肿瘤活性。
