Abstract 4217: Effect of HDAC3 targeting on endometrial cancer progression and therapeutic potential

Abstract Endometrial cancer (EC) exerts a considerable burden on women’s health worldwide. Epigenetic dysregulation is often reported in the development and progression of various cancers. A negative regulator of PI3K signaling and frequently found to be mutated in human EC is PTEN whereas HDAC3 is critical in cell survival, proliferation, differentiation, and cancer development. HDAC inhibitors are being explored as an epigenetic treatment option, but their effects in EC are not well characterized. Pgrcre/+Hdac3f/fPtenf/f (Hdac3d/dPtend/d) mice were generated and histopathologic analysis was performed to examine the effect of Hdac3 ablation on EC with Pten deficiency. Hdac3d/dPtend/d mice revealed remarkably delayed tumorigenesis of EC compared to Ptend/dmice. To evaluate the effect of HDAC3 inhibitor (RGFP966), 6-week-old Ptend/d(Stage l EC) mice were treated with vehicle (sunflower oil) or RGFP966 (10mg/kg) twice per week for 5 weeks by intraperitoneal injection. The effect of EC progression wasexamined by immunohistochemistry using proliferation and apoptosis markers. In RGFP966-treated Ptend/dmice, uterine/body weight ratio (average 22.56±2.99) was significantly (p< 0.05) decreased compared to vehicle-treated Ptend/d mice (66.78 ± 10.11). Immunohistochemistry revealed a significant reduction of proliferation marker and a significant increase of apoptosis marker in RGFP966 treatment compared to vehicle. Furthermore, the level of pAKT and pERK1/2 was substantially reduced in RGFP966 treatment group. These results demonstrate that HDAC3 targeting impedes the pathogenesis of EC and RGFP966 delays EC progression. Citation Format: Keun Cheon Kim, Dunston Krystina, Hall Amanda, Hunter I Mark, Tae Hoon Kim, jaewook Jeong. Effect of HDAC3 targeting on endometrial cancer progression and therapeutic potential [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 4217.