ONC201治疗H3K27M突变的中线弥漫性胶质瘤的临床疗效源于对整合代谢和表观遗传途径的干扰。
Clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas is driven by disruption of integrated metabolic and epigenetic pathways.
发表日期：2023 Aug 16
作者：
Sriram Venneti, Abed Rahman Kawakibi, Sunjong Ji, Sebastian M Waszak, Stefan R Sweha, Mateus Mota, Matthew Pun, Akash Deogharkar, Chan Chung, Rohinton S Tarapore, Samuel Ramage, Andrew Chi, Patrick Y Wen, Isabel Arrillaga-Romany, Tracy T Batchelor, Nicholas A Butowski, Ashley Sumrall, Nicole Shonka, Rebecca A Harrison, John de Groot, Minesh Mehta, Matthew D Hall, Doured Daghistani, Timothy F Cloughesy, Benjamin M Ellingson, Kevin Beccaria, Pascale Varlet, Michelle M Kim, Yoshie Umemura, Hugh Garton, Andrea Franson, Jonathan Schwartz, Rajan Jain, Maureen Kachman, Heidi Baum, Charles F Burant, Sophie L Mottl, Rodrigo T Cartaxo, Vishal John, Dana Messinger, Tingting Qin, Erik Peterson, Peter Sajjakulnukit, Karthik Ravi, Alyssa Waugh, Dustin Walling, Yujie Ding, Ziyun Xia, Anna Schwendeman, Debra Hawes, Fusheng Yang, Alexander R Judkins, Daniel Wahl, Costas A Lyssiotis, Daniel de la Nava, Marta M Alonso, Augustine Eze, Jasper Spitzer, Susanne V Schmidt, Ryan J Duchatel, Matthew D Dun, Jason E Cain, Li Jiang, Sylwia A Stopka, Gerard Baquer, Michael S Regan, Mariella G Filbin, Nathalie Y R Agar, Lili Zhao, Chandan Kumar-Sinha, Rajen Mody, Arul Chinnaiyan, Ryo Kurokawa, Drew Pratt, Viveka N Yadav, Jacques Grill, Cassie Kline, Sabine Mueller, Adam Resnick, Javad Nazarian, Joshua E Allen, Yazmin Odia, Sharon L Gardner, Carl Koschmann
来源：
Epigenetics & Chromatin
摘要：
H3K27M突变的弥漫中线胶质瘤（DMG）患者目前没有经过验证的有效治疗方法。ONC201最近在这些患者中显示出了疗效，但其背后的机制尚不清楚。我们从两项已经完成的多中心临床研究中评估了接受治疗的患者的临床结果、肿瘤测序以及组织/脑脊液相关样本。在初始放疗后但复发之前接受ONC201治疗的患者中，中位总生存期为21.7个月，而在复发后接受治疗的患者中，中位总生存期为9.3个月。基线肿瘤测序显示，放射影像学反应与关键三羧酸循环相关基因的表达增加相关。ONC201治疗增加了培养的H3K27M-DMG细胞和患者脑脊液样本中的2-羟基戊二酸水平。这与体外和人类肿瘤中H3K27me3的增加相关，并伴随着细胞周期调控和神经胶质分化基因的表观遗传下调。总的来说，ONC201通过干扰综合代谢和表观遗传途径，并逆转病态特征性H3K27me3的减少，在H3K27M-DMG中显示出了疗效。
H3K27M-mutant diffuse midline glioma (DMG) patients have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/CSF correlate samples from patients treated in two completed multi-site clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, while 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 neuro-glial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction.