PDF(Pubmed)
Abstract：
Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options. Among them, H3 K27-altered diffuse midline gliomas (DMG) of the brainstem stand out due to their distinct molecular features and dismal prognosis. Recent advances in molecular profiling techniques have unveiled the critical role of H3 K27 alterations, particularly a lysine-to-methionine mutation on position 27 (K27M) of the histone H3 tail, in the pathogenesis of DMG. These mutations result in epigenetic dysregulation, which leads to altered chromatin structure and gene expression patterns in DMG tumor cells, ultimately contributing to the aggressive phenotype of DMG. The exploration of targeted therapeutic avenues for DMG has gained momentum in recent years. Therapies, including epigenetic modifiers, kinase inhibitors, and immunotherapies, are under active investigation; these approaches aim to disrupt aberrant signaling cascades and overcome the various mechanisms of therapeutic resistance in DMG. Challenges, including blood-brain barrier penetration and DMG tumor heterogeneity, require innovative approaches to improve drug delivery and personalized treatment strategies. This review aims to provide a comprehensive overview of the evolving understanding of DMG, focusing on the intricate molecular mechanisms driving tumorigenesis/tumor progression and the current landscape of emerging targeted interventions.
摘要：
小儿高级别神经胶质瘤是脑肿瘤的破坏性子集，其特点是积极的病理生理学和有限的治疗选择。其中,H3K27改变的脑干弥漫性中线胶质瘤（DMG）由于其独特的分子特征和预后不良而脱颖而出。分子谱分析技术的最新进展揭示了H3K27改变的关键作用，特别是在组蛋白H3尾的位置27（K27M）上的赖氨酸到甲硫氨酸突变，在DMG的发病机制中。这些突变导致表观遗传失调，导致DMG肿瘤细胞中染色质结构和基因表达模式的改变，最终导致DMG的侵袭性表型。近年来，针对DMG的靶向治疗途径的探索取得了势头。Therapies,包括表观遗传修饰剂，激酶抑制剂，和免疫疗法，正在积极研究;这些方法旨在破坏异常信号级联并克服DMG中治疗抗性的各种机制。挑战,包括血脑屏障穿透和DMG肿瘤异质性，需要创新的方法来改善药物输送和个性化治疗策略。这篇综述旨在全面概述对DMG的不断发展的理解，关注驱动肿瘤发生/肿瘤进展的复杂分子机制以及新兴的靶向干预措施的现状。
