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

Evangeline R Jackson; Ryan J Duchatel; Dilana E Staudt; Mika L Persson; Abdul Mannan; Sridevi Yadavilli; Sarah Parackal; Shaye Game; Wai Chin Chong; W Samantha N Jayasekara; Marion Le Grand; Padraic S Kearney; Alicia M Douglas; Izac J Findlay; Zacary P Germon; Holly P McEwen; Tyrone S Beitaki; Adjanie Patabendige; David A Skerrett-Byrne; Brett Nixon; Nathan D Smith; Bryan Day; Neevika Manoharan; Sumanth Nagabushan; Jordan R Hansford; Dinisha Govender; Geoff B McCowage; Ron Firestein; Meegan Howlett; Raelene Endersby; Nicholas G Gottardo; Frank Alvaro; Sebastian M Waszak; Martin R Larsen; Yolanda Colino-Sanguino; Fatima Valdes-Mora; Andria Rakotomalala; Samuel Meignan; Eddy Pasquier; Nicolas André; Esther Hulleman; David D Eisenstat; Nicholas A Vitanza; Javad Nazarian; Carl Koschmann; Sabine Mueller; Jason E Cain; Matthew D Dun

doi:10.1158/0008-5472.CAN-23-0186

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

Cancer Res. 2023 May 17:OF1-OF17. doi: 10.1158/0008-5472.CAN-23-0186. Online ahead of print.

Authors

Evangeline R Jackson^#^{1

2}, Ryan J Duchatel^#^{1

2}, Dilana E Staudt^#^{1

2}, Mika L Persson^{1

2}, Abdul Mannan^{1

2}, Sridevi Yadavilli^{3

4}, Sarah Parackal^{5

6}, Shaye Game^{5

6}, Wai Chin Chong^{5

6}, W Samantha N Jayasekara^{5

6}, Marion Le Grand⁷, Padraic S Kearney^{1

2}, Alicia M Douglas^{1

2}, Izac J Findlay^{1

2}, Zacary P Germon^{1

2}, Holly P McEwen^{1

2}, Tyrone S Beitaki^{1

2}, Adjanie Patabendige^{8

9}, David A Skerrett-Byrne^{10

11}, Brett Nixon^{10

11}, Nathan D Smith¹², Bryan Day¹³, Neevika Manoharan¹⁴, Sumanth Nagabushan¹⁴, Jordan R Hansford¹⁵, Dinisha Govender¹⁶, Geoff B McCowage¹⁶, Ron Firestein^{5

6}, Meegan Howlett¹⁷, Raelene Endersby¹⁷, Nicholas G Gottardo^{17

18}, Frank Alvaro^{2

19}, Sebastian M Waszak^{20

21}, Martin R Larsen²², Yolanda Colino-Sanguino^{23

24}, Fatima Valdes-Mora^{23

24}, Andria Rakotomalala^{25

26}, Samuel Meignan^{25

26}, Eddy Pasquier^{7

27}, Nicolas André^{7

27

28}, Esther Hulleman²⁹, David D Eisenstat^{30

31}, Nicholas A Vitanza^{32

33}, Javad Nazarian^{3

34

35}, Carl Koschmann³⁶, Sabine Mueller^{34

37}, Jason E Cain^{5

6}, Matthew D Dun^{1

2

38}

Affiliations

¹ Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
² Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
³ Center for Genetic Medicine Research, Children's National Hospital, Washington, DC.
⁴ Brain Tumor Institute, Children's National Hospital, Washington, DC.
⁵ Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
⁶ Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
⁷ Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, Marseille, France.
⁸ Brain Barriers Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
⁹ Department of Biology, Edge Hill University, Ormskirk, United Kingdom.
¹⁰ School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia.
¹¹ Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
¹² Analytical and Biomolecular Research Facility Advanced Mass Spectrometry Unit, University of Newcastle, Callaghan, New South Wales, Australia.
¹³ QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
¹⁴ Department of Paediatric Oncology, Sydney Children's Hospital, Randwick, New South Wales, Australia.
¹⁵ Michael 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 Department of Oncology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁷ Brain Tumor Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.
¹⁸ Department of Pediatric and Adolescent Oncology and Hematology, Perth Children's Hospital, Perth, Australia.
¹⁹ John Hunter Children's Hospital, New Lambton Heights, New South Wales, Australia.
²⁰ Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
²¹ Department of Neurology, University of California, San Francisco, San Francisco, California.
²² Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
²³ Cancer Epigenetics Biology and Therapeutics, Precision Medicine Theme, Children's Cancer Institute, Sydney, New South Wales, Australia.
²⁴ School of Women's and Children's Health, University of NSW, Sydney, New South Wales, Australia.
²⁵ Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, Lille, France.
²⁶ University of Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277, CANTHER, Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.
²⁷ Metronomics Global Health Initiative, Marseille, France.
²⁸ Department of Pediatric Oncology, La Timone Children's Hospital, AP-HM, Marseille, France.
²⁹ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
³⁰ Children's Cancer Centre, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
³¹ Neuro-Oncology Laboratory, Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
³² Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington.
³³ Division of Pediatric Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington.
³⁴ Department of Pediatrics, University Children's Hospital Zurich, Zurich, Switzerland.
³⁵ The George Washington University, School of Medicine and Health Sciences, Washington, DC.
³⁶ Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
³⁷ Department of Neurology, Neurosurgery and Pediatric, University of California, San Francisco, California.
³⁸ Paediatric Program, Mark Hughes Foundation Centre for Brain Cancer Research, College of Health, Medicine, and Wellbeing, Callaghan, New South Wales, Australia.

^# Contributed equally.

PMID: 37195023
DOI: 10.1158/0008-5472.CAN-23-0186

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.

Associated data

ClinicalTrials.gov/NCT05009992