University of Michigan, Ann Arbor, Michigan.
University of California, San Francisco, San Francisco, California.
Cancer Discov. 2023 Nov 1;13(11):2370-2393. doi: 10.1158/2159-8290.CD-23-0131.
Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction.
The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.
患有 H3K27M 突变弥漫性中线神经胶质瘤（DMG）的患者目前尚无经证实有效的治疗方法。ONC201 最近在这些患者中显示出疗效，但这一发现的背后机制尚不清楚。我们评估了在两项已完成的多中心临床研究中接受治疗的患者的临床结局、肿瘤测序以及组织/脑脊液（CSF）相关样本。在初始放疗后但在复发前接受 ONC201 治疗的患者中位总生存期为 21.7 个月，而在复发后接受治疗的患者中位总生存期为 9.3 个月。影像学反应与基线肿瘤测序中关键三羧酸循环相关基因表达增加有关。ONC201 治疗增加了培养的 H3K27M-DMG 细胞和患者 CSF 样本中的 2-羟基戊二酸水平。这与体外抑制性 H3K27me3 增加以及人类肿瘤中的表观遗传下调细胞周期调节和神经胶质分化基因相对应。总体而言，ONC201 通过破坏整合的代谢和表观遗传途径并逆转特征性 H3K27me3 减少来显示出在 H3K27M-DMG 中的疗效。
本研究中包含的临床、影像学和分子分析表明 ONC201 在 H3K27M 突变型 DMG 中的疗效，并支持 ONC201 作为首个单药疗法，可改善 H3K27M 突变型 DMG 的预后，超出放疗效果。从机制上讲，ONC201 破坏整合的代谢和表观遗传途径，并逆转特征性 H3K27me3 减少。本文选自本期精选文章，第 2293 页。
