Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
01 11 2023
01 11 2023
Historique:
received:
29
01
2023
revised:
30
05
2023
accepted:
10
08
2023
medline:
2
11
2023
pubmed:
16
8
2023
entrez:
16
8
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37584601
pii: 728431
doi: 10.1158/2159-8290.CD-23-0131
pmc: PMC10618742
mid: NIHMS1925902
doi:
Substances chimiques
Histones
0
TIC10 compound
9U35A31JAI
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2370-2393Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG006508
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA279984
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA261926
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS119231
Pays : United States
Organisme : NCI NIH HHS
ID : R44 CA192427
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA270027
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS110572
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK089503
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK097153
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS124607
Pays : United States
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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