Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
Authors: Venneti Sriram , Kawakibi Abed Rahman , Ji Sunjong , Waszak Sebastian M. , Sweha Stefan R. , Mota Mateus , Pun Matthew , Deogharkar Akash , Chung Chan , Tarapore Rohinton S. , Ramage Samuel , Chi Andrew , Wen Patrick Y. , Arrillaga-Romany Isabel , Batchelor Tracy T. , Butowski Nicholas A. , Sumrall Ashley , Shonka Nicole , Harrison Rebecca A. , de Groot John , Mehta Minesh , Hall Matthew D. , Daghistani Doured , Cloughesy Timothy F. , Ellingson Benjamin M. , Beccaria Kevin , Varlet Pascale , Kim Michelle M. , Umemura Yoshie , Garton Hugh , Franson Andrea , Schwartz Jonathan , Jain Rajan , Kachman Maureen , Baum Heidi , Burant Charles F. , Mottl Sophie L. , Cartaxo Rodrigo T. , John Vishal , Messinger Dana , Qin Tingting , Peterson Erik , Sajjakulnukit Peter , Ravi Karthik , Waugh Alyssa , Walling Dustin , Ding Yujie , Xia Ziyun , Schwendeman Anna , Hawes Debra , Yang Fusheng , Judkins Alexander R. , Wahl Daniel , Lyssiotis Costas A. , de la Nava Daniel , Alonso Marta M. , Eze Augustine , Spitzer Jasper , Schmidt Susanne V. , Duchatel Ryan J. , Dun Matthew D. , Cain Jason E. , Jiang Li , Stopka Sylwia A. , Baquer Gerard , Regan Michael S. , Filbin Mariella G. , Agar Nathalie Y.R. , Zhao Lili , Kumar-Sinha Chandan , Mody Rajen , Chinnaiyan Arul , Kurokawa Ryo , Pratt Drew , Yadav Viveka N. , Grill Jacques , Kline Cassie , Mueller Sabine , Resnick Adam , Nazarian Javad , Allen Joshua E. , Odia Yazmin , Gardner Sharon L. , Koschmann Carl 
Published: August 2023

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.

Significance:

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