弥漫性中线神经胶质瘤（DMGs）是毁灭性的儿童脑肿瘤，被认为是儿童癌症相关死亡的主要原因。DMGs是在中线诊断出的高级别神经胶质瘤（HGGs）。Euchromatin是DMG的标志性特征，其由于H3K27全局低甲基化而引起，可能通过组蛋白H3基因（H3K27M）的点突变或过表达抑制因子zeste同源物抑制蛋白（EZHIP）而引起。在一项针对进行性HGGs的成人的临床试验中，一位22岁的有丘脑H3K27改变的DMG患者对dordaviprone（ONC201）表现出显著的临床和影像学反应。H3K27改变的HGG患者的这种反应，以及无基因型H3肿瘤患者无反应，增加了dordaviprone用于DMG治疗的临床兴趣。此外，还出现了有关临床效益的其他报告，但研究机制行动（MOA）落后于dordaviprone的临床应用，对反应生物标志物未解决。在这里，我们总结了dordaviprone的安全性，研究了它的临床前MOA--鉴定线粒体蛋白酶'ClpP'作为反应生物标志物，并讨论了其他ClpP激动剂，扩大了对抗DMG的潜在武器库。最后，我们讨论了包括ClpP激动剂在内的联合策略，以及其免疫调节效应，暗示了肿瘤微环境在DMG患者反应中的作用。©The Author(s) 2023. 由牛津大学出版社代表神经肿瘤学协会出版。

Diffuse midline gliomas (DMGs) are devastating pediatric brain tumors recognized as the leading cause of cancer-related death in children. DMGs are high-grade gliomas (HGGs) diagnosed along the brain's midline. Euchromatin is the hallmark feature of DMG, caused by global hypomethylation of H3K27 either through point mutations in histone H3 genes (H3K27M), or by overexpression of the enhancer of zeste homolog inhibitory protein (EZHIP). In a clinical trial for adults with progressive HGGs, a 22-year-old patient with a thalamic H3K27-altered DMG, showed remarkable clinical and radiological responses to dordaviprone (ONC201). This response in a H3K27-altered HGG patient, coupled with the lack of response of patients harboring wildtype-H3 tumors, has increased the clinical interest in dordaviprone for the treatment of DMG. Additional reports of clinical benefit have emerged, but research defining mechanisms of action (MOA) fall behind dordaviprone's clinical use, with biomarkers of response unresolved. Here, we summarize dordaviprone's safety, interrogate its preclinical MOA- identifying the mitochondrial protease 'ClpP' as a biomarker of response, and discuss other ClpP-agonists, expanding the arsenal of potential weapons in the fight against DMG. Finally, we discuss combination strategies including ClpP-agonists, and its immunomodulatory effects suggestive of a role for the tumor microenvironment in DMG patients' response.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.