Enhancing the effect of class I HDAC inhibition in MYC amplified group 3 medulloblastoma with novel drug combinations

Medulloblastoma (MB) is a highly aggressive pediatric brain tumor. Patients with Group 3 MB tumors harboring an amplification of the oncogene MYC exhibit a worse prognosis compared to patients with non-MYC amplified Group 3 tumors. We and others have previously demonstrated that MYC amplified Group 3 MB cells show high sensitivity towards class I histone deacetylase (HDAC) inhibition with entinostat (MS-275) in vitro. To identify drugs suitable for combination treatment (entinostat + X) of MYC amplified Group 3 MB we performed a drug screen with a library of n = 75 compounds as single agents and in combination with entinostat in n = 4 MB cell lines (MYC amplified vs. MYC-non amplified). To gain further inside in pathways altered upon class I HDAC inhibition we determined changes in protein quantity, phosphorylation and acetylation in an array based proteomic profiling of entinostat treated MYC amplified HD-MB03 cells. The drug screen revealed n = 20/75 drugs that were particularly effective in combination with entinostat treatment in the three MYC amplified cell lines. We selected three top hit drugs for further assessment. Experiments to determine drug synergy are currently ongoing.

Publication History

Article published online:
13 May 2020