Synergistic Effects of Quisinostat and ZE94-0605 in Ovarian Cancer Models

Ovarian cancer remains a lethal malignancy with high recurrence rates and drug resistance, despite multimodal treatments utilizing cytoreductive surgery and platinum-based chemotherapy. Quisinostat, a second-generation histone deacetylase (HDAC) inhibitor, has shown promise in solid tumors, synergizing with platinum agents by enhancing DNA adduct formation and double-strand breaks. However, dose-limiting toxicities have historically hindered broader clinical adoption. We previously reported the discovery and preclinical evaluation of ZE94-0605 in ovarian, breast, and brain tumors. Herein, we report the synergistic effects of combining Quisinostat and ZE94-0605 in OVCAR-3 xenograft models. Methods: OVCAR-3 human ovarian cancer cells were harvested during log-phase growth. Female athymic nude mice (6-8 weeks) were injected subcutaneously in the flank with 5×10^6 cells suspended 1:1 in Matrigel. Following tumor establishment, mice were randomized (n=8-10/group) into cohorts receiving vehicle, ZE94-0605, quisinostat, or the combination. Agents were administered via oral gavage once daily at doses selected to ensure sub-toxic yet pharmacologically active exposures. Tumor volumes and body weights were recorded 2-3 times per week; tumor growth inhibition (TGI) was calculated relative to the vehicle group at study end. Animals were euthanized upon reaching predetermined size limits or upon study conclusion. Statistical analyses utilized one-way ANOVA with appropriate post hoc comparisons. All procedures complied with institutional IACUC and national animal care guidelines. Results: While single-agent treatment produced measurable antitumor activity, the combination of ZE94-0605 and quisinostat elicited the most pronounced response. ZE94-0605 monotherapy induced a moderate reduction in tumor growth compared with vehicle, resulting in partial TGI. Quisinostat alone showed greater activity than ZE94-0605, confirming HDAC inhibition is effective in this platinum-sensitive model. Notably, the combination produced synergistic antitumor effects, leading to marked suppression of tumor progression throughout the dosing period. Combination-treated tumors exhibited significantly smaller volumes relative to either monotherapy group (p < 0.01), and several animals demonstrated tumor stasis or regression. The calculated TGI at study end was highest in the combination arm. Body weight monitoring revealed no significant toxicity in any group, and the combination was well-tolerated with no overt adverse effects. Conclusion: Combining quisinostat with the CDK2 inhibitor ZE94-0605 yields synergistic efficacy and superior outcomes in the OVCAR-3 xenograft model. Our findings indicate that quisinostat enhances in vivo therapeutic efficacy and supports further evaluation of this combination strategy for ovarian and other cancers. Citation Format: Boris Rogovoy, Dmitrii Shkil, Ruben Karapetian, Elena Bulanova, Sergey Shevyakov, Vladislav Parchinsky, Tudor Oprea, Amy Burd, Iain Dukes, Nikolay Savchuk. Synergy evaluation of quisinostat (HDAC I Inhibitor) and ZE94-0605 (CDK2 Inhibitor) in various in vitro and in vivo models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1266.