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Abstract：
Background Diffuse midline glioma (DMG) is a devastating pediatric brain tumor unresponsive to hundreds of clinical trials. Approximately 80% of DMGs harbor H3K27M oncohistones, which reprogram the epigenome to increase the metabolic profile of the tumor cells. Methods We have previously shown preclinical efficacy of targeting both oxidative phosphorylation and glycolysis through treatment with ONC201, which activates the mitochondrial protease ClpP, and paxalisib, which inhibits PI3K/mTOR, respectively. Results ONC201 and paxalisib combination treatment aimed at inducing metabolic distress led to the design of the first DMG-specific platform trial PNOC022 (NCT05009992). Conclusions Here, we expand on the PNOC022 rationale and discuss various considerations, including liquid biome, microbiome, and genomic biomarkers, quality-of-life endpoints, and novel imaging modalities, such that we offer direction on future clinical trials in DMG.
摘要：
弥漫性中线神经胶质瘤（DMG）是一种破坏性的小儿脑肿瘤，对数百项临床试验无反应。大约80%的DMGs含有H3K27M致癌蛋白，重新编程表观基因组以增加肿瘤细胞的代谢谱。我们之前已经显示了通过用ONC201治疗靶向氧化磷酸化和糖酵解的临床前功效，ONC201可以激活线粒体蛋白酶ClpP，还有Paxalisib,抑制PI3K/mTOR，分别。这种旨在诱导代谢窘迫的组合治疗导致了第一个DMG特异性平台试验PNOC022(NCT05009992)的设计。这里,我们扩展PNOC022的基本原理并讨论各种考虑因素，包括液体生物群落，微生物组,和基因组生物标志物，生活质量终点，和新颖的成像方式，这样我们就为DMG未来的临床试验提供了方向。
