EXTH-58. Long-term treatment with mutant IDH inhibitor DS-1001b suppresses tumor growth and induces epigenetic reprogramming in IDH1-mutant gliomas

BACKGROUND Heterozygous mutations in isocitrate dehydrogenase (IDH) 1 and 2 represent defining molecular alterations in astrocytoma, IDH-mutant, and oligodendroglioma, IDH-mutant, as classified by the World Health Organization Classification of Tumors of the Central Nervous System, 5th Edition. These mutations result in neomorphic enzymatic activity that converts α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), leading to widespread epigenetic dysregulation. In this study, we assessed the therapeutic potential of DS-1001b, a selective inhibitor of mutant IDH1 (R132H and R132C), using IDH1 R132H-mutant glioma cell lines and xenograft models. METHODS We examined the growth-inhibitory effects of DS-1001b in vitro and in vivo using three IDH1 R132H-mutant glioma models: MGG152, BT142, and A1074. The impact of long-term DS-1001b exposure on transcriptional programs, epigenetic landscape, and cellular metabolism was also analyzed through RNA-seq, ChIP-seq, DNA methylation profiling, and metabolomic assays. RESULTS DS-1001b treatment markedly suppressed 2-HG production in both cultured glioma cells and xenograft tumors. In intracranial models derived from A1074 and BT142, DS-1001b significantly extended survival (p = 0.0064 and p = 0.0004, respectively). Prolonged treatment (6 months) partially reversed global DNA hypermethylation patterns. Integrated analyses of RNA sequencing, ChIP sequencing, and DNA methylation data revealed that DS-1001b-induced changes in H3K4me3 enrichment were closely associated with alterations in gene expression. Furthermore, metabolomic profiling indicated a significant reduction in asparagine levels in A1074 cells after prolonged DS-1001b administration. CONCLUSIONS These findings demonstrated that sustained inhibition of mutant IDH1 with DS-1001b exerted antitumor effects in IDH1-mutant gliomas both in vitro and in vivo, accompanied by changes in transcriptomic and epigenetic profiles.