Microtubule-targeting combined with HDAC inhibition is a novel therapeutic strategy for Diffuse Intrinsic Pontine Gliomas.

Diffuse Intrinsic Pontine Gliomas (DIPGs) are an incurable childhood brain cancer for which novel treatments are needed. DIPGs are characterised by a mutation in the H3 histone (H3K27M), resulting in loss of H3K27 methylation and global gene dysregulation. TRX-E-009-1 is a novel anti-cancer agent with preclinical activity demonstrated against a range of cancers. We examined the anti-tumour activity of TRX-E-009-1 against DIPG neurosphere cultures and observed tumour-specific activity with IC50s ranging from 20-100 nM, while no activity was observed against normal human astrocyte cells. TRX-E-009-1 exerted its anti-proliferative effect through the induction of apoptotic pathways, with marked increases in cleaved caspase 3 and cleaved PARP levels, whilst also restoring histone H3K27me3 methylation. Co-administration of TRX-E-009-1 and the histone deacetylase (HDAC) inhibitor SAHA extended survival in DIPG orthotopic animal models. This antitumour effect was further enhanced with irradiation. Our findings indicate that TRX-E-009-1, combined with HDAC inhibition, represents a novel, potent therapy for children with DIPG.