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

Authors

Sriram Venneti, University of Michigan, Ann Arbor, Michigan.
Abed Rahman Kawakibi, University of Michigan, Ann Arbor, Michigan.
Sunjong Ji, University of Michigan, Ann Arbor, Michigan.
Sebastian M. Waszak, University of California, San Francisco, San Francisco, California.
Stefan R. Sweha, University of Michigan, Ann Arbor, Michigan.
Mateus Mota, University of Michigan, Ann Arbor, Michigan.
Matthew Pun, University of Michigan, Ann Arbor, Michigan.
Akash Deogharkar, University of Michigan, Ann Arbor, Michigan.
Chan Chung, University of Michigan, Ann Arbor, Michigan.
Rohinton S. Tarapore, Chimerix, Inc., Durham, North Carolina.
Samuel Ramage, Chimerix, Inc., Durham, North Carolina.
Andrew Chi, NYU Langone Health, New York, New York.
Patrick Y. Wen, Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.
Isabel Arrillaga-Romany, Massachusetts General Hospital, Boston, Massachusetts.
Tracy T. Batchelor, Brigham and Women's Hospital, Boston, Massachusetts.
Nicholas A. Butowski, University of California, San Francisco, San Francisco, California.
Ashley Sumrall, Levine Cancer Institute, Charlotte, North Carolina.
Nicole Shonka, Mayo Clinic, Rochester, Minnesota.
Rebecca A. Harrison, BC Cancer, The University of British Columbia, Vancouver, BC, Canada.
John de Groot, University of California, San Francisco, San Francisco, California.
Minesh Mehta, Miami Cancer Institute, Miami, Florida.
Matthew D. Hall, Miami Cancer Institute, Miami, Florida.
Doured Daghistani, Miami Cancer Institute, Miami, Florida.
Timothy F. Cloughesy, University of California, Los Angeles, Los Angeles, California.
Benjamin M. Ellingson, University of California, Los Angeles, Los Angeles, California.
Kevin Beccaria, Department of Neurosurgery, Necker Sick Children's University Hospital and Paris Descartes University, Paris, France.
Pascale Varlet, Department of Neuropathology, Sainte-Anne Hospital and Paris Descartes University, Paris, France.
Michelle M. Kim, University of Michigan, Ann Arbor, Michigan.
Yoshie Umemura, University of Michigan, Ann Arbor, Michigan.
Hugh Garton, University of Michigan, Ann Arbor, Michigan.
Andrea Franson, University of Michigan, Ann Arbor, Michigan.
Jonathan Schwartz, Mayo Clinic, Rochester, Minnesota.

Document Type

Journal Article

Publication Date

11-1-2023

Journal

Cancer discovery

Volume

13

Issue

11

DOI

10.1158/2159-8290.CD-23-0131

Abstract

UNLABELLED: 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.

APA Citation

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; and Schwartz, Jonathan, "Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways" (2023). GW Authored Works. Paper 3894.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3894

Department

Genomics and Precision Medicine