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ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma.
Jackson, Evangeline R; Duchatel, Ryan J; Staudt, Dilana E; Persson, Mika L; Mannan, Abdul; Yadavilli, Sridevi; Parackal, Sarah; Game, Shaye; Chong, Wai Chin; Jayasekara, W Samantha N; Grand, Marion Le; Kearney, Padraic S; Douglas, Alicia M; Findlay, Izac J; Germon, Zacary P; McEwen, Holly P; Beitaki, Tyrone S; Patabendige, Adjanie; Skerrett-Byrne, David A; Nixon, Brett; Smith, Nathan D; Day, Bryan; Manoharan, Neevika; Nagabushan, Sumanth; Hansford, Jordan R; Govender, Dinisha; McCowage, Geoff B; Firestein, Ron; Howlett, Meegan; Endersby, Raelene; Gottardo, Nicholas G; Alvaro, Frank; Waszak, Sebastian M; Larsen, Martin R; Colino-Sanguino, Yolanda; Valdes-Mora, Fatima; Rakotomalala, Andria; Meignan, Samuel; Pasquier, Eddy; André, Nicolas; Hulleman, Esther; Eisenstat, David D; Vitanza, Nicholas A; Nazarian, Javad; Koschmann, Carl; Mueller, Sabine; Cain, Jason E; Dun, Matthew D.
Afiliação
  • Jackson ER; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Duchatel RJ; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Staudt DE; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Persson ML; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Mannan A; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Yadavilli S; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Parackal S; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Game S; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Chong WC; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Jayasekara WSN; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Grand ML; Center for Genetic Medicine Research, Children's National Hospital, Washington, DC.
  • Kearney PS; Brain Tumor Institute, Children's National Hospital, Washington, DC.
  • Douglas AM; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
  • Findlay IJ; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
  • Germon ZP; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
  • McEwen HP; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
  • Beitaki TS; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
  • Patabendige A; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
  • Skerrett-Byrne DA; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
  • Nixon B; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
  • Smith ND; Centre de Recherche en Cancérologie de Marseille, Aix-Marseille Université, Inserm, CNRS, Institut Paoli Calmettes, Marseille, France.
  • Day B; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Manoharan N; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Nagabushan S; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Hansford JR; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Govender D; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • McCowage GB; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Firestein R; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Howlett M; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Endersby R; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Gottardo NG; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Alvaro F; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Waszak SM; Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Larsen MR; Brain Barriers Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.
  • Colino-Sanguino Y; Department of Biology, Edge Hill University, Ormskirk, United Kingdom.
  • Valdes-Mora F; School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia.
  • Rakotomalala A; Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • Meignan S; School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia.
  • Pasquier E; Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
  • André N; Analytical and Biomolecular Research Facility Advanced Mass Spectrometry Unit, University of Newcastle, Callaghan, New South Wales, Australia.
  • Hulleman E; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
  • Eisenstat DD; Department of Paediatric Oncology, Sydney Children's Hospital, Randwick, New South Wales, Australia.
  • Vitanza NA; Department of Paediatric Oncology, Sydney Children's Hospital, Randwick, New South Wales, Australia.
  • Nazarian J; 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.
  • Koschmann C; Department of Oncology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
  • Mueller S; Department of Oncology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
  • Cain JE; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
  • Dun MD; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
Cancer Res ; : OF1-OF17, 2023 May 17.
Article em En | MEDLINE | ID: mdl-37195023
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.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article