Abstract 3069: Inhibition of PGE2 signaling by an EP2/4 dual antagonist OCT-598 prevents acquisition of therapy-resistance and tumor relapse

Abstract Conventional antitumor drug discovery focuses primarily on selective killing of cancer cells. However, more often than not, cancer cells become resistant to the therapy and tumors eventually relapse in a more malignant form, potentially even accelerating disease progression afterwards. Therefore, it is of paramount importance to curtail the process by which cancer cells adapt to the therapeutic pressure to re-invent themselves and regenerate. Prostaglandin E2 (PGE2) is widely recognized as an important mediator of wound healing and tissue regeneration after injury by orchestrating reparative immune responses and mobilizing tissue stem cells. Likewise, in cancer, the PGE2 pathway has been shown to promote tumor growth, immune evasion, angiogenesis, and cancer stem cell (CSC) survival. Thus, upon cytotoxic insults, the apoptotic signal in dying cells induces PGE2 production, which enables, in a paracrine manner, the surviving cells to persist and eventually repopulate. Therefore, blockade of the PGE2 signals concurrently with cell-killing is anticipated to prevent tumors from acquiring therapy resistance. Of the known PGE2 receptors EP1-4, EP2 and EP4 are best known to convey its pro-tumor and immune-evasive signals. OCT-598 is a potent and selective dual antagonist of EP2 and EP4 with Ki values of 23 nM and 0.2 nM vs EP2 and EP4, respectively. OCT-598 has been shown previously to elicit complete regression in a mouse syngeneic TC-1 tumor model when used in conjunction with the standard of care chemo-immunotherapy regimen (Abstract 3234, AACR 2023). In this study, we present “anti-resistance” activities of OCT-598. In vitro, chemotherapy-induced cell deaths are followed by a dormant period, where the ‘un-dead’ cells show enlarged morphology and hyperploidy, and subsequently by repopulation of smaller, proliferative para-diploid cells. Addition of OCT-598 along with the chemotherapeutic agent decreased the number of the transient, enlarged cells and inhibited eventual repopulation in a dose-dependent manner. In vivo, OCT-598 abrogated tumor relapse after irradiation in CT26 mouse syngeneic tumor model, leading to complete remissions. Based on these observations, a clinical trial is set to be initiated to test the “anti-resistance” activity of OCT-598 as an adjuvant to the standard-of-care treatment in patients with advanced solid tumors. Citation Format: Youngrae Lee, Haein Choi, Jong-Won Lim, Sung Eun Lee, Yeeun Kim, Changhoon Choi, Taeyoung Yoon. Inhibition of PGE2 signaling by an EP2/4 dual antagonist OCT-598 prevents acquisition of therapy-resistance and tumor relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3069.