Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways-Reference-Cited by-同舟云学术

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

Published:2023-08-11 Issue:11 Volume:13 Page:2370-2393
ISSN:2159-8274
Container-title:Cancer Discovery
language:en
Short-container-title:

Author:

Venneti Sriram¹^ORCID,Kawakibi Abed Rahman¹^ORCID,Ji Sunjong¹^ORCID,Waszak Sebastian M.²³⁴^ORCID,Sweha Stefan R.¹⁵^ORCID,Mota Mateus¹^ORCID,Pun Matthew¹^ORCID,Deogharkar Akash¹^ORCID,Chung Chan¹⁶^ORCID,Tarapore Rohinton S.⁷^ORCID,Ramage Samuel⁷^ORCID,Chi Andrew⁸^ORCID,Wen Patrick Y.⁹^ORCID,Arrillaga-Romany Isabel¹⁰^ORCID,Batchelor Tracy T.¹¹^ORCID,Butowski Nicholas A.²^ORCID,Sumrall Ashley¹²^ORCID,Shonka Nicole¹³^ORCID,Harrison Rebecca A.¹⁴^ORCID,de Groot John²^ORCID,Mehta Minesh¹⁵^ORCID,Hall Matthew D.¹⁵^ORCID,Daghistani Doured¹⁵^ORCID,Cloughesy Timothy F.¹⁶^ORCID,Ellingson Benjamin M.¹⁶^ORCID,Beccaria Kevin¹⁷^ORCID,Varlet Pascale¹⁸^ORCID,Kim Michelle M.¹^ORCID,Umemura Yoshie¹^ORCID,Garton Hugh¹^ORCID,Franson Andrea¹^ORCID,Schwartz Jonathan¹³^ORCID,Jain Rajan⁸^ORCID,Kachman Maureen¹^ORCID,Baum Heidi¹^ORCID,Burant Charles F.¹^ORCID,Mottl Sophie L.³^ORCID,Cartaxo Rodrigo T.¹^ORCID,John Vishal¹^ORCID,Messinger Dana¹^ORCID,Qin Tingting¹^ORCID,Peterson Erik¹^ORCID,Sajjakulnukit Peter¹^ORCID,Ravi Karthik¹^ORCID,Waugh Alyssa¹^ORCID,Walling Dustin¹^ORCID,Ding Yujie¹^ORCID,Xia Ziyun¹^ORCID,Schwendeman Anna¹^ORCID,Hawes Debra¹⁹^ORCID,Yang Fusheng¹⁹^ORCID,Judkins Alexander R.¹⁹^ORCID,Wahl Daniel¹^ORCID,Lyssiotis Costas A.¹^ORCID,de la Nava Daniel²⁰²¹²²^ORCID,Alonso Marta M.²⁰²¹²²^ORCID,Eze Augustine²³^ORCID,Spitzer Jasper²⁴²⁵^ORCID,Schmidt Susanne V.²⁴²⁵^ORCID,Duchatel Ryan J.²⁶²⁷²⁸^ORCID,Dun Matthew D.²⁶²⁷²⁸^ORCID,Cain Jason E.²⁹³⁰^ORCID,Jiang Li³¹³²^ORCID,Stopka Sylwia A.³³³⁴^ORCID,Baquer Gerard³³^ORCID,Regan Michael S.³³^ORCID,Filbin Mariella G.³¹³²^ORCID,Agar Nathalie Y.R.³³³⁴³⁵^ORCID,Zhao Lili¹^ORCID,Kumar-Sinha Chandan¹^ORCID,Mody Rajen¹^ORCID,Chinnaiyan Arul¹^ORCID,Kurokawa Ryo¹³⁶^ORCID,Pratt Drew³⁷^ORCID,Yadav Viveka N.³⁸^ORCID,Grill Jacques³⁹^ORCID,Kline Cassie⁴⁰⁴¹^ORCID,Mueller Sabine²⁴²^ORCID,Resnick Adam⁴⁰⁴¹^ORCID,Nazarian Javad⁴³⁴⁴⁴⁵^ORCID,Allen Joshua E.⁷^ORCID,Odia Yazmin¹⁵^ORCID,Gardner Sharon L.⁸^ORCID,Koschmann Carl¹^ORCID

Affiliation:

1. 1University of Michigan, Ann Arbor, Michigan.

2. 2University of California, San Francisco, San Francisco, California.

3. 3Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.

4. 4Laboratory of Computational Neuro-Oncology, Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

5. 5Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.

6. 6Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea.

7. 7Chimerix, Inc., Durham, North Carolina.

8. 8NYU Langone Health, New York, New York.

9. 9Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.

10. 10Massachusetts General Hospital, Boston, Massachusetts.

11. 11Brigham and Women's Hospital, Boston, Massachusetts.

12. 12Levine Cancer Institute, Charlotte, North Carolina.

13. 13Mayo Clinic, Rochester, Minnesota.

14. 14BC Cancer, The University of British Columbia, Vancouver, BC, Canada.

15. 15Miami Cancer Institute, Miami, Florida.

16. 16University of California, Los Angeles, Los Angeles, California.

17. 17Department of Neurosurgery, Necker Sick Children's University Hospital and Paris Descartes University, Paris, France.

18. 18Department of Neuropathology, Sainte-Anne Hospital and Paris Descartes University, Paris, France.

19. 19Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California.

20. 20Health Research Institute of Navarra (IdiSNA), Pamplona, Spain.

21. 21Solid Tumor Program, Cima Universidad de Navarra, Pamplona, Spain.

22. 22Department of Pediatrics, Clínica Universidad de Navarra, Pamplona, Spain.

23. 23Center for Genetic Medicine Research, Children's National Hospital, Washington, DC.

24. 24Institute of Innate Immunity, AG Immunogenomics, University Hospital Bonn, Bonn, Germany.

25. 25Institute of Clinical Chemistry and Clinical Pharmacology, AG Immunmonitoring and Genomics, University Hospital Bonn, Bonn, Germany.

26. 26Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.

27. 27Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.

28. 28Paediatric Program, Mark Hughes Foundation Centre for Brain Cancer Research, College of Health, Medicine, and Wellbeing, Callaghan, NSW, Australia.

29. 29Hudson Institute of Medical Research, Clayton, VIC, Australia.

30. 30Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia.

31. 31Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Boston, Massachusetts.

32. 32Harvard Medical School, Boston, Massachusetts.

33. 33Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

34. 34Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

35. 35Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.

36. 36The University of Tokyo, Tokyo, Japan.

37. 37Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

38. 38Department of Pediatrics at Children's Mercy Research Institute, Kansas City, Missouri.

39. 39Department of Pediatric and Adolescent Oncology and INSERM Unit 981, Gustave Roussy and University Paris-Saclay, Villejuif, France.

40. 40Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

41. 41University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

42. 42Department of Oncology, Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

43. 43Department of Pediatrics, Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

44. 44Research Center for Genetic Medicine, Children's National Hospital, Washington, DC.

45. 45George Washington University School of Medicine and Health Sciences, Washington, DC.

Abstract

AbstractPatients 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

Funder

National Institutes of Health

U.S. Department of Defense

University of Michigan Chad Carr Pediatric Brain Tumor Center

The Evans Family

ChadTough Defeat DIPG Foundation

Catching Up with Jack

Pediatric Brain Tumor Foundation

Prayers from Maria

Michael Miller Memorial Foundation

Morgan Behen Golf Classic

Yuvaan Tiwari Foundation