Abstract 1838: Optimal epigenetic therapies in triple-negative breast cancer.

Abstract Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer and is characterized by a very high recurrence rate. The primary treatment for this cancer type is systemic chemotherapy, often combined with immunotherapy. However, these treatments typically result in only short-term responses. Recent experimental studies have highlighted the critical role of chromatin modifications, such as DNA methylation and histone modifications, in TNBC development and progression. Consistent with these findings, epigenetic therapies targeting these modifications have shown promise in preclinical and early clinical studies. Building on these insights, we developed a predictive computational modeling platform to gain a deeper understanding of how different chromatin modifications influence TNBC and to identify optimal therapeutic strategies targeting these modifications. The platform integrates experimental data, pharmacokinetics, and mechanistic insights into the role of chromatin regulation in TNBC. We focused on therapies combining an EZH2 inhibitor, which reduces the establishment of repressive H3K27me3 marks and promotes chromatin opening, and an AKT inhibitor, which enhances the expression of GATA3 and BMF. Using this framework, we confirmed the experimentally observed synergy between the two inhibitors and uncovered its mechanistic basis: EZH2 inhibition quickly reaches a plateau once chromatin becomes fully accessible, whereas the effect of AKT inhibition increases more gradually across a broader concentration range. In-silico clinical trials involving 1,500 virtual patients further showed that optimized combination schedules markedly outperform monotherapies. Based on these predictions, we conducted in-vitro experiments using live-cell imaging, which validated the model’s predictions on how different inhibitor doses and combinations shape treatment response, and confirmed the combination regimen identified by the platform as optimal. Beyond TNBC, the generalizable framework developed here can potentially be adapted to other types of cancer in which chromatin modifications play a similar role. This research can then also help establish the basis for the discovery of common therapeutic targets, contributing to a broader range of cancer treatment strategies. Overall, this research could lead to the development of novel, more effective, and more durable treatment strategies for TNBC, thereby improving patient outcomes and providing new possibilities for cancer therapy research. Citation Format: Simone Bruno, Alexandra Indeglia, Sophia Lichterfeld, Karen M. Cichowski, Franziska Michor. Optimal epigenetic therapies in triple-negative breast cancer 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 1838.