Abstract SY23-01: Diffuse midline gliomas: From cell cycle to therapeutic opportunities

Abstract The fatal Diffuse Midline Gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3. K27M impairs normal development by stalling of differentiation. As replication timing influences gene expression, cell fate, and cellular response to therapeutics, we undertook a multi-omics approach (Repli-seq, cell cycle RNA-seq, single cell RNA-seq) in DMG cells (H3.1K27M and H3.3K27M subgroups) and tumors in comparison to normal brain to gain an appreciation for targetable pathways in DMG. DMG cells presented differential replication timing in each subgroup, which, in turn, correlated with significant differential gene expression including the cholesterol biosynthesis pathway. Consistent with these findings, DMG tumors presented high replication stress and cholesterol biosynthesis pathway signatures. Moreover, DMG cells were specifically vulnerable to an inhibitor of the cholesterol pathway and to a replication stress therapy, singly and in combination. In conclusion, this combinatorial genomics approach revealed insights into therapeutic opportunities for this incurable disease. Citation Format: Anastasia E. Hains, Joana G. Marques, Kashish Chetal, Tsunetoshi Nakatani, Andreas Ettinger, Carlos A. O Biagi, Adriana Gonzalez-Sandoval, Renjitha Pillai, Alberto Gatto, Maria-Elena Torres-Padilla, Ruslan I. Sadreyev, Mariella G. Filbin, Capucine Van Rechem. Diffuse midline gliomas: From cell cycle to therapeutic opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY23-01.