MARS-seq on SU-DIPG13 cells treated Sulfopin/Vorinostat/Sulfopin+Vorinostat or DMSO

Diffuse midline gliomas (DMG) are aggressive pediatric tumors of the central nervous system that are highly resistant to treatments and are inevitably fatal. Lysine to methionine substitution of residue 27 on histone H3 (H3-K27M) is a driver mutation in DMGs, reshaping the epigenetic landscape of these cells to promote tumorigenesis. H3-K27M gliomas are characterized by deregulation of histone acetylation and methylation pathways, as well as the oncogenic MYC pathway. In search of effective treatment, we examined the therapeutic potential of dual targeting of histone deacetylases (HDACs) and MYC in these tumors. Treatment of H3-K27M patient-derived cells with Sulfopin, an inhibitor shown to block MYC-driven tumors in vivo, in combination with the HDAC inhibitor Vorinostat, resulted in substantial decrease in cell viability. Moreover, transcriptome and epigenome profiling revealed synergistic effect of this drug combination in downregulation of prominent oncogenic pathways such as mTOR. Finally, in vivo studies of patient-derived orthotopic xenograft models showed significant tumor size reduction in mice treated with the drug combination. These results highlight the combined treatment of Sulfopin and Vorinostat as a promising therapeutic approach for these aggressive tumors.