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

Autor:	Venneti S; University of Michigan, Ann Arbor, Michigan., Kawakibi AR; University of Michigan, Ann Arbor, Michigan., Ji S; University of Michigan, Ann Arbor, Michigan., Waszak SM; University of California, San Francisco, San Francisco, California.; Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.; Laboratory of Computational Neuro-Oncology, Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland., Sweha SR; University of Michigan, Ann Arbor, Michigan.; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York., Mota M; University of Michigan, Ann Arbor, Michigan., Pun M; University of Michigan, Ann Arbor, Michigan., Deogharkar A; University of Michigan, Ann Arbor, Michigan., Chung C; University of Michigan, Ann Arbor, Michigan.; Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea., Tarapore RS; Chimerix, Inc., Durham, North Carolina., Ramage S; Chimerix, Inc., Durham, North Carolina., Chi A; NYU Langone Health, New York, New York., Wen PY; Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts., Arrillaga-Romany I; Massachusetts General Hospital, Boston, Massachusetts., Batchelor TT; Brigham and Women's Hospital, Boston, Massachusetts., Butowski NA; University of California, San Francisco, San Francisco, California., Sumrall A; Levine Cancer Institute, Charlotte, North Carolina., Shonka N; Mayo Clinic, Rochester, Minnesota., Harrison RA; BC Cancer, The University of British Columbia, Vancouver, BC, Canada., de Groot J; University of California, San Francisco, San Francisco, California., Mehta M; Miami Cancer Institute, Miami, Florida., Hall MD; Miami Cancer Institute, Miami, Florida., Daghistani D; Miami Cancer Institute, Miami, Florida., Cloughesy TF; University of California, Los Angeles, Los Angeles, California., Ellingson BM; University of California, Los Angeles, Los Angeles, California., Beccaria K; Department of Neurosurgery, Necker Sick Children's University Hospital and Paris Descartes University, Paris, France., Varlet P; Department of Neuropathology, Sainte-Anne Hospital and Paris Descartes University, Paris, France., Kim MM; University of Michigan, Ann Arbor, Michigan., Umemura Y; University of Michigan, Ann Arbor, Michigan., Garton H; University of Michigan, Ann Arbor, Michigan., Franson A; University of Michigan, Ann Arbor, Michigan., Schwartz J; Mayo Clinic, Rochester, Minnesota., Jain R; NYU Langone Health, New York, New York., Kachman M; University of Michigan, Ann Arbor, Michigan., Baum H; University of Michigan, Ann Arbor, Michigan., Burant CF; University of Michigan, Ann Arbor, Michigan., Mottl SL; Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway., Cartaxo RT; University of Michigan, Ann Arbor, Michigan., John V; University of Michigan, Ann Arbor, Michigan., Messinger D; University of Michigan, Ann Arbor, Michigan., Qin T; University of Michigan, Ann Arbor, Michigan., Peterson E; University of Michigan, Ann Arbor, Michigan., Sajjakulnukit P; University of Michigan, Ann Arbor, Michigan., Ravi K; University of Michigan, Ann Arbor, Michigan., Waugh A; University of Michigan, Ann Arbor, Michigan., Walling D; University of Michigan, Ann Arbor, Michigan., Ding Y; University of Michigan, Ann Arbor, Michigan., Xia Z; University of Michigan, Ann Arbor, Michigan., Schwendeman A; University of Michigan, Ann Arbor, Michigan., Hawes D; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California., Yang F; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California., Judkins AR; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California., Wahl D; University of Michigan, Ann Arbor, Michigan., Lyssiotis CA; University of Michigan, Ann Arbor, Michigan., de la Nava D; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain.; Solid Tumor Program, Cima Universidad de Navarra, Pamplona, Spain.; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain., Alonso MM; Health Research Institute of Navarra (IdiSNA), Pamplona, Spain.; Solid Tumor Program, Cima Universidad de Navarra, Pamplona, Spain.; Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain., Eze A; Center for Genetic Medicine Research, Children's National Hospital, Washington, DC., Spitzer J; Institute of Innate Immunity, AG Immunogenomics, University Hospital Bonn, Bonn, Germany.; Institute of Clinical Chemistry and Clinical Pharmacology, AG Immunmonitoring and Genomics, University Hospital Bonn, Bonn, Germany., Schmidt SV; Institute of Innate Immunity, AG Immunogenomics, University Hospital Bonn, Bonn, Germany.; Institute of Clinical Chemistry and Clinical Pharmacology, AG Immunmonitoring and Genomics, University Hospital Bonn, Bonn, Germany., Duchatel RJ; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.; Paediatric Program, Mark Hughes Foundation Centre for Brain Cancer Research, College of Health, Medicine, and Wellbeing, Callaghan, NSW, Australia., Dun MD; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.; Paediatric Program, Mark Hughes Foundation Centre for Brain Cancer Research, College of Health, Medicine, and Wellbeing, Callaghan, NSW, Australia., Cain JE; Hudson Institute of Medical Research, Clayton, VIC, Australia.; Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia., Jiang L; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Stopka SA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Baquer G; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Regan MS; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Filbin MG; Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Agar NYR; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts., Zhao L; University of Michigan, Ann Arbor, Michigan., Kumar-Sinha C; University of Michigan, Ann Arbor, Michigan., Mody R; University of Michigan, Ann Arbor, Michigan., Chinnaiyan A; University of Michigan, Ann Arbor, Michigan., Kurokawa R; University of Michigan, Ann Arbor, Michigan.; The University of Tokyo, Tokyo, Japan., Pratt D; Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Yadav VN; Department of Pediatrics at Children's Mercy Research Institute, Kansas City, Missouri., Grill J; Department of Pediatric and Adolescent Oncology and INSERM Unit 981, Gustave Roussy and University Paris-Saclay, Villejuif, France., Kline C; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania., Mueller S; University of California, San Francisco, San Francisco, California.; Department of Oncology, Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland., Resnick A; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania., Nazarian J; Department of Pediatrics, Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.; Research Center for Genetic Medicine, Children's National Hospital, Washington, DC.; George Washington University School of Medicine and Health Sciences, Washington, DC., Allen JE; Chimerix, Inc., Durham, North Carolina., Odia Y; Miami Cancer Institute, Miami, Florida., Gardner SL; NYU Langone Health, New York, New York., Koschmann C; University of Michigan, Ann Arbor, Michigan.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2023 Nov 01; Vol. 13 (11), pp. 2370-2393.
DOI:	10.1158/2159-8290.CD-23-0131
Abstrakt:	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. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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