Functional analysis of class I HDAC inhibition in group 3 medulloblastoma to identify synergistic drug combinations

Medulloblastoma (MB) is a highly aggressive childhood brain tumour. Patients with Group 3 MB harbouring a MYC-amplification show particularly poor outcome. We and others have previously shown that MYC-amplified MBs are highly susceptible towards class I histone deacetylase inhibition (HDACi). In clinical trials HDACi monotherapy shows only modest efficacy in solid tumours. We here delineate the molecular effects of class I HDACi in MB to identify potentially synergistic drug combinations. The MYC-amplified MB cell line HD-MB03 was treated with class I HDACi entinostat. Transcriptional changes were determined by gene expression profiling, qPCR and western blot and functionally assessed using Gene Set Enrichment Analysis, Ingenuity Pathway Analysis and Cytoscape. Entinostat treatment evokes up/downregulation of various pharmacologically targetable biomechanisms including MHC-antigen processing, vesicle processing, DNA damage, RNA processing, cell cycle, p53 and kinase signalling. We hypothesize a synergistic effect of entinostat and agents targeting these biomechanisms. In vitro synergy studies in MYC-amplified vs. non MYC-amplified MB cell lines are currently ongoing.