Constitutional mismatch repair deficiency (CMMRD)是一种与儿童高度突变恶性胶质瘤发展相关的癌症易感综合征，并且具有不良预后。尽管已经报道了对于弥散性固有性桥脑胶质瘤（DIPG）的治疗性组蛋白去乙酰化酶（HDAC）抑制剂的研究，但在这里，我们使用了一个临床相关的活检源突变高强度DIPG模型（PBT-24FH）和一个CRISPR-Cas9诱导的遗传模型，评估了HDAC抑制剂对于突变高强度DIPG的疗效。我们在体外筛选了PBT-24FH细胞对一组HDAC抑制剂（HDACis）的敏感性，发现两种相关的HDAC抑制剂与纳摩尔级IC50相关联，分别是奎喜诺替（27 nM）和罗米地平（2 nM）。在体内，奎喜诺替表现出更高的疗效，在PBT-24FH侧腹模型中诱导了近乎完全的肿瘤消退。RNA测序显示奎喜诺替驱动的基因表达显著变化，包括神经元和促炎基因的上调。为了验证奎喜诺替对其他突变高强度DIPG模型体内的潜在效力，我们在基因诱导的错配修复（MMR）缺陷DIPG侧腹肿瘤中测试了奎喜诺替，结果表明MMR功能丧失增加了体内奎喜诺替的敏感性。在这里，我们建立了奎喜诺替对突变高强度DIPG的临床前疗效，支持进一步研究使用遗传上皮靶向突变高强度儿科癌症的潜力进行临床翻译。这些发现支持进一步研究HDAC抑制剂在桥脑高级别胶质瘤以及其他突变高强度中枢神经系统肿瘤中的应用，不仅限于组蛋白突变。版权所有 © 2023. 由Elsevier Inc.出版。

Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of diffuse intrinsic pontine glioma (DIPG) has been reported; here, we use a clinically relevant biopsy-derived hypermutant DIPG model (PBT-24FH) and a CRISPR-Cas9 induced genetic model to evaluate the efficacy of HDAC inhibition against hypermutant DIPG. We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM). In vivo, quisinostat proved more efficacious, inducing near-complete tumor regression in a PBT-24FH flank model. RNA sequencing revealed significant quisinostat-driven changes in gene expression, including upregulation of neural and pro-inflammatory genes. To validate the observed potency of quisinostat in vivo against additional hypermutant DIPG models, we tested quisinostat in genetically-induced mismatch repair (MMR)-deficient DIPG flank tumors, demonstrating that loss of MMR function increases sensitivity to quisinostat in vivo. Here, we establish the preclinical efficacy of quisinostat against hypermutant DIPG, supporting further investigation of epigenetic targeting of hypermutant pediatric cancers with the potential for clinical translation. These findings support further investigation of HDAC inhibitors against pontine high-grade gliomas, beyond only those with histone mutations, as well as against other hypermutant central nervous system tumors.Copyright © 2023. Published by Elsevier Inc.