ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma-Reference-Cited by-同舟云学术

ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma

Published:2023-05-05 Issue:14 Volume:83 Page:2421-2437
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Jackson Evangeline R.¹²^ORCID,Duchatel Ryan J.¹²^ORCID,Staudt Dilana E.¹²^ORCID,Persson Mika L.¹²^ORCID,Mannan Abdul¹²^ORCID,Yadavilli Sridevi³⁴^ORCID,Parackal Sarah⁵⁶^ORCID,Game Shaye⁵⁶^ORCID,Chong Wai Chin⁵⁶^ORCID,Jayasekara W. Samantha N.⁵⁶^ORCID,Grand Marion Le⁷^ORCID,Kearney Padraic S.¹²^ORCID,Douglas Alicia M.¹²^ORCID,Findlay Izac J.¹²^ORCID,Germon Zacary P.¹²^ORCID,McEwen Holly P.¹²^ORCID,Beitaki Tyrone S.¹²^ORCID,Patabendige Adjanie⁸⁹^ORCID,Skerrett-Byrne David A.¹⁰¹¹^ORCID,Nixon Brett¹⁰¹¹^ORCID,Smith Nathan D.¹²^ORCID,Day Bryan¹³^ORCID,Manoharan Neevika¹⁴^ORCID,Nagabushan Sumanth¹⁴^ORCID,Hansford Jordan R.¹⁵^ORCID,Govender Dinisha¹⁶^ORCID,McCowage Geoff B.¹⁶^ORCID,Firestein Ron⁵⁶^ORCID,Howlett Meegan¹⁷^ORCID,Endersby Raelene¹⁷^ORCID,Gottardo Nicholas G.¹⁷¹⁸^ORCID,Alvaro Frank²¹⁹^ORCID,Waszak Sebastian M.²⁰²¹^ORCID,Larsen Martin R.²²^ORCID,Colino-Sanguino Yolanda²³²⁴^ORCID,Valdes-Mora Fatima²³²⁴^ORCID,Rakotomalala Andria²⁵²⁶^ORCID,Meignan Samuel²⁵²⁶^ORCID,Pasquier Eddy⁷²⁷^ORCID,André Nicolas⁷²⁷²⁸^ORCID,Hulleman Esther²⁹^ORCID,Eisenstat David D.³⁰³¹^ORCID,Vitanza Nicholas A.³²³³^ORCID,Nazarian Javad³³⁴³⁵^ORCID,Koschmann Carl³⁶^ORCID,Mueller Sabine³⁴³⁷^ORCID,Cain Jason E.⁵⁶^ORCID,Dun Matthew D.¹²³⁸^ORCID

Affiliation:

1. 1Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.

2. 2Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.

3. 3Center for Genetic Medicine Research, Children's National Hospital, Washington, DC.

4. 4Brain Tumor Institute, Children's National Hospital, Washington, DC.

5. 5Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

6. 6Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.

7. 7Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, Marseille, France.

8. 8Brain Barriers Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.

9. 9Department of Biology, Edge Hill University, Ormskirk, United Kingdom.

10. 10School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia.

11. 11Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.

12. 12Analytical and Biomolecular Research Facility Advanced Mass Spectrometry Unit, University of Newcastle, Callaghan, New South Wales, Australia.

13. 13QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

14. 14Department of Paediatric Oncology, Sydney Children's Hospital, Randwick, New South Wales, Australia.

15. 15Michael Rice Cancer Centre, Women's and Children's Hospital, South Australia Health and Medical Research Institute, South Australia ImmunoGenomics Cancer Institute, University of Adelaide, Adelaide, Australia.

16. 16Department of Oncology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.

17. 17Brain Tumor Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.

18. 18Department of Pediatric and Adolescent Oncology and Hematology, Perth Children's Hospital, Perth, Australia.

19. 19John Hunter Children's Hospital, New Lambton Heights, New South Wales, Australia.

20. 20Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.

21. 21Department of Neurology, University of California, San Francisco, San Francisco, California.

22. 22Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.

23. 23Cancer Epigenetics Biology and Therapeutics, Precision Medicine Theme, Children's Cancer Institute, Sydney, New South Wales, Australia.

24. 24School of Women's and Children's Health, University of NSW, Sydney, New South Wales, Australia.

25. 25Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, Lille, France.

26. 26University of Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277, CANTHER, Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.

27. 27Metronomics Global Health Initiative, Marseille, France.

28. 28Department of Pediatric Oncology, La Timone Children's Hospital, AP-HM, Marseille, France.

29. 29Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

30. 30Children's Cancer Centre, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.

31. 31Neuro-Oncology Laboratory, Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.

32. 32Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington.

33. 33Division of Pediatric Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington.

34. 34Department of Pediatrics, University Children's Hospital Zurich, Zurich, Switzerland.

35. 35The George Washington University, School of Medicine and Health Sciences, Washington, DC.

36. 36Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.

37. 37Department of Neurology, Neurosurgery and Pediatric, University of California, San Francisco, California.

38. 38Paediatric Program, Mark Hughes Foundation Centre for Brain Cancer Research, College of Health, Medicine, and Wellbeing, Callaghan, New South Wales, Australia.

Abstract

Abstract Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.

Funder

National Health and Medical Research Council

ChadTough Foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Link

https://aacrjournals.org/cancerres/article-pdf/doi/10.1158/0008-5472.CAN-23-0186/3329963/can-23-0186.pdf

Reference59 articles.

1. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014;Ostrom;Neuro Oncol,2017

2. Diffuse intrinsic pontine glioma: poised for progress;Warren;Front Oncol,2012