Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
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- Sriram Venneti
- 1University of Michigan, Ann Arbor, Michigan.
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- Abed Rahman Kawakibi
- 1University of Michigan, Ann Arbor, Michigan.
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- Sunjong Ji
- 1University of Michigan, Ann Arbor, Michigan.
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- Sebastian M. Waszak
- 2University of California, San Francisco, San Francisco, California.
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- Stefan R. Sweha
- 1University of Michigan, Ann Arbor, Michigan.
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- Mateus Mota
- 1University of Michigan, Ann Arbor, Michigan.
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- Matthew Pun
- 1University of Michigan, Ann Arbor, Michigan.
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- Akash Deogharkar
- 1University of Michigan, Ann Arbor, Michigan.
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- Chan Chung
- 1University of Michigan, Ann Arbor, Michigan.
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- Rohinton S. Tarapore
- 7Chimerix, Inc., Durham, North Carolina.
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- Samuel Ramage
- 7Chimerix, Inc., Durham, North Carolina.
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- Andrew Chi
- 8NYU Langone Health, New York, New York.
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- Patrick Y. Wen
- 9Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.
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- Isabel Arrillaga-Romany
- 10Massachusetts General Hospital, Boston, Massachusetts.
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- Tracy T. Batchelor
- 11Brigham and Women's Hospital, Boston, Massachusetts.
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- Nicholas A. Butowski
- 2University of California, San Francisco, San Francisco, California.
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- Ashley Sumrall
- 12Levine Cancer Institute, Charlotte, North Carolina.
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- Nicole Shonka
- 13Mayo Clinic, Rochester, Minnesota.
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- Rebecca A. Harrison
- 14BC Cancer, The University of British Columbia, Vancouver, BC, Canada.
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- John de Groot
- 2University of California, San Francisco, San Francisco, California.
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- Minesh Mehta
- 15Miami Cancer Institute, Miami, Florida.
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- Matthew D. Hall
- 15Miami Cancer Institute, Miami, Florida.
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- Doured Daghistani
- 15Miami Cancer Institute, Miami, Florida.
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- Timothy F. Cloughesy
- 16University of California, Los Angeles, Los Angeles, California.
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- Benjamin M. Ellingson
- 16University of California, Los Angeles, Los Angeles, California.
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- Kevin Beccaria
- 17Department of Neurosurgery, Necker Sick Children's University Hospital and Paris Descartes University, Paris, France.
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- Pascale Varlet
- 18Department of Neuropathology, Sainte-Anne Hospital and Paris Descartes University, Paris, France.
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- Michelle M. Kim
- 1University of Michigan, Ann Arbor, Michigan.
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- Yoshie Umemura
- 1University of Michigan, Ann Arbor, Michigan.
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- Hugh Garton
- 1University of Michigan, Ann Arbor, Michigan.
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- Andrea Franson
- 1University of Michigan, Ann Arbor, Michigan.
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- Jonathan Schwartz
- 13Mayo Clinic, Rochester, Minnesota.
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- Rajan Jain
- 8NYU Langone Health, New York, New York.
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- Maureen Kachman
- 1University of Michigan, Ann Arbor, Michigan.
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- Heidi Baum
- 1University of Michigan, Ann Arbor, Michigan.
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- Charles F. Burant
- 1University of Michigan, Ann Arbor, Michigan.
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- Sophie L. Mottl
- 3Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
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- Rodrigo T. Cartaxo
- 1University of Michigan, Ann Arbor, Michigan.
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- Vishal John
- 1University of Michigan, Ann Arbor, Michigan.
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- Dana Messinger
- 1University of Michigan, Ann Arbor, Michigan.
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- Tingting Qin
- 1University of Michigan, Ann Arbor, Michigan.
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- Erik Peterson
- 1University of Michigan, Ann Arbor, Michigan.
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- Peter Sajjakulnukit
- 1University of Michigan, Ann Arbor, Michigan.
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- Karthik Ravi
- 1University of Michigan, Ann Arbor, Michigan.
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- Alyssa Waugh
- 1University of Michigan, Ann Arbor, Michigan.
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- Dustin Walling
- 1University of Michigan, Ann Arbor, Michigan.
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- Yujie Ding
- 1University of Michigan, Ann Arbor, Michigan.
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- Ziyun Xia
- 1University of Michigan, Ann Arbor, Michigan.
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- Anna Schwendeman
- 1University of Michigan, Ann Arbor, Michigan.
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- Debra Hawes
- 19Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
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- Fusheng Yang
- 19Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
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- Alexander R. Judkins
- 19Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.
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- Daniel Wahl
- 1University of Michigan, Ann Arbor, Michigan.
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- Costas A. Lyssiotis
- 1University of Michigan, Ann Arbor, Michigan.
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- Daniel de la Nava
- 20Health Research Institute of Navarra (IdiSNA), Pamplona, Spain.
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- Marta M. Alonso
- 20Health Research Institute of Navarra (IdiSNA), Pamplona, Spain.
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- Augustine Eze
- 23Center for Genetic Medicine Research, Children's National Hospital, Washington, DC.
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- Jasper Spitzer
- 24Institute of Innate Immunity, AG Immunogenomics, University Hospital Bonn, Bonn, Germany.
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- Susanne V. Schmidt
- 24Institute of Innate Immunity, AG Immunogenomics, University Hospital Bonn, Bonn, Germany.
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- Ryan J. Duchatel
- 26Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.
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- Matthew D. Dun
- 26Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.
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- Jason E. Cain
- 29Hudson Institute of Medical Research, Clayton, VIC, Australia.
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- Li Jiang
- 31Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, Massachusetts.
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- Sylwia A. Stopka
- 33Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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- Gerard Baquer
- 33Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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- Michael S. Regan
- 33Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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- Mariella G. Filbin
- 31Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, Massachusetts.
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- Nathalie Y.R. Agar
- 33Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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- Lili Zhao
- 1University of Michigan, Ann Arbor, Michigan.
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- Chandan Kumar-Sinha
- 1University of Michigan, Ann Arbor, Michigan.
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- Rajen Mody
- 1University of Michigan, Ann Arbor, Michigan.
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- Arul Chinnaiyan
- 1University of Michigan, Ann Arbor, Michigan.
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- Ryo Kurokawa
- 1University of Michigan, Ann Arbor, Michigan.
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- Drew Pratt
- 37Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
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- Viveka N. Yadav
- 38Department of Pediatrics at Children's Mercy Research Institute, Kansas City, Missouri.
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- Jacques Grill
- 39Department of Pediatric and Adolescent Oncology and INSERM Unit 981, Gustave Roussy and University Paris-Saclay, Villejuif, France.
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- Cassie Kline
- 40Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
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- Sabine Mueller
- 2University of California, San Francisco, San Francisco, California.
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- Adam Resnick
- 40Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
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- Javad Nazarian
- 43Department of Pediatrics, Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
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- Joshua E. Allen
- 7Chimerix, Inc., Durham, North Carolina.
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- Yazmin Odia
- 15Miami Cancer Institute, Miami, Florida.
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- Sharon L. Gardner
- 8NYU Langone Health, New York, New York.
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- Carl Koschmann
- 1University of Michigan, Ann Arbor, Michigan.
説明
<jats:title>Abstract</jats:title><jats:sec><jats:title /><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Significance:</jats:title><jats:p>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.</jats:p><jats:p>This article is featured in Selected Articles from This Issue, p. 2293</jats:p></jats:sec>
収録刊行物
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- Cancer Discovery
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Cancer Discovery 13 (11), 2370-2393, 2023-08-11
American Association for Cancer Research (AACR)
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詳細情報 詳細情報について
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- CRID
- 1360302868773606016
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- ISSN
- 21598290
- 21598274
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- PubMed
- 37584601
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- Web Site
- https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-23-0131/3355982/cd-23-0131.pdf
- https://aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-23-0131/3364436/cd-23-0131.pdf
- https://aacrjournals.org/cancerdiscovery/article-pdf/13/11/2370/3378471/2370.pdf
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