Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.

Sriram Venneti ,Matthew D Hall ,Ryo Kurokawa ,Benjamin M Ellingson ,Costas A Lyssiotis ,Rajen Mody ,Alyssa Waugh ,Chan Chung ,Chandan Kumar‐Sinha ,Minesh P Mehta ,Lili Zhao ,Timothy F Cloughesy ,Michael S Regan ,Jasper Spitzer ,Maureen Kachman ,Mateus Mota ,Adam Resnick ,Daniel De La Nava ,Susanne V Schmidt ,Andrea Franson ,Arul M Chinnaiyan ,Dana Messinger ,Peter Sajjakulnukit ,Daniel Wahl ,Sophie L Mottl ,Tracy T Batchelor ,Abed Rahman Kawakibi ,Nicole Shonka ,Yujie Ding ,Vishal John ,Debra Hawes ,Sabine Mueller ,Pascale Varlet ,Rebecca Harrison ,Nathalie Y.r Agar ,Sharon Gardner ,Akash Deogharkar ,Mariella G Filbin ,Sylwia A Stopka ,Ryan J Duchatel ,Jason E Cain ,Heidi Baum ,Ashley Sumrall ,Stefan R Sweha ,Hugh Garton ,Joshua E Allen ,Kévin Beccaria ,Nicholas Butowski ,Dustin Walling ,Michelle M Kim ,Matthew Pun ,Erik Peterson ,Anna Schwendeman ,Rajan Jain ,Javad Nazarian ,Andrew Chi ,Yoshie Umemura ,Gerard Baquer ,Augustine Eze ,Doured Daghistani ,Marta M Alonso ,Sebastian M Waszak ,Viveka Nand Yadav ,Ziyun Xia ,Samuel Ramage ,Cassie Kline ,Charles F Burant ,Patrick Y Wen ,Matthew D Dun ,Rodrigo T Cartaxo ,John De Groot ,Yazmín Odia ,Fusheng Yang ,Jonathan Schwartz ,Karthik Ravi ,Isabel Arrillaga‐Romany ,Rohinton S Tarapore ,Li Jiang ,Jacques Grill ,Alexander R Judkins ,Drew Pratt ,Tingting Qin ,Sunjong Ji ,Carl Koschmann

doi:10.1158/2159-8290.cd-23-0131

Abstract

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.

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