弥漫性内在桥脑胶质母细胞瘤(DIPG)是一种无法治愈的儿童脑癌，需要新的治疗方法。DIPG的特征是H3组蛋白的突变(H3K27M)，导致H3K27甲基化的丧失和全局基因失调。TRX-E-009-1是一种新型抗癌药物，在多种癌症中已经展示了临床前活性。我们研究了TRX-E-009-1对DIPG神经球培养的抗肿瘤活性，并观察到特异性的抗肿瘤活性，IC50值范围为20-100 nM，而对正常人星形胶质细胞没有活性。TRX-E-009-1通过诱导凋亡通路发挥其抗增殖效应，同时显著增加了剪切的caspase 3和剪切的PARP水平，同时恢复了H3K27me3组蛋白的甲基化。TRX-E-009-1与组蛋白去乙酰化酶(HDAC)抑制剂SAHA联合应用延长了DIPG原位动物模型的存活时间。辐照进一步增强了这种抗肿瘤效果。我们的发现表明，TRX-E-009-1与HDAC抑制剂的联合应用为DIPG患儿提供了一种新的、有效的治疗方法。

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.