Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Cancer Discovery Année : 2023

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

Sriram Venneti
Abed Rahman Kawakibi
Sunjong Ji
Sebastian Waszak
Stefan Sweha
Matthew Pun
Akash Deogharkar
Chan Chung
Rohinton Tarapore
Samuel Ramage
Andrew Chi
Isabel Arrillaga-Romany
Tracy Batchelor
Nicholas Butowski
Ashley Sumrall
Nicole Shonka
Rebecca Harrison
Minesh Mehta
Matthew Hall
Doured Daghistani
Timothy Cloughesy
Benjamin Ellingson
Kevin Beccaria
Pascale Varlet
Michelle Kim
Yoshie Umemura
Hugh Garton
Andrea Franson
Jonathan Schwartz
Rajan Jain
Maureen Kachman
Heidi Baum
Charles Burant
Sophie Mottl
Rodrigo 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 Judkins
Daniel Wahl
Costas Lyssiotis
Daniel de la Nava
Marta Alonso
Augustine Eze
Jasper Spitzer
Susanne Schmidt
Ryan Duchatel
Matthew Dun
Jason Cain
Li Jiang
Sylwia Stopka
Gerard Baquer
Michael Regan
Mariella Filbin
Nathalie Y.R. Agar
Lili Zhao
Chandan Kumar-Sinha
Rajen Mody
Arul Chinnaiyan
Ryo Kurokawa
Drew Pratt
Viveka Yadav
Cassie Kline
Sabine Mueller
Adam Resnick
Javad Nazarian
Joshua Allen
Yazmin Odia
Sharon Gardner
Carl Koschmann

Résumé

Abstract 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

Dates et versions

hal-04493048 , version 1 (06-03-2024)

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Citer

Sriram Venneti, Abed Rahman Kawakibi, Sunjong Ji, Sebastian Waszak, Stefan Sweha, et al.. Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways. Cancer Discovery, 2023, 13 (11), pp.2370-2393. ⟨10.1158/2159-8290.CD-23-0131⟩. ⟨hal-04493048⟩
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