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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 Nilanthi; Le Grand, Marion; 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, Geoffrey B; Firestein, Ron; Howlett, Meegan; Endersby, Raelene; Gottardo, Nicholas G; Alvaro, Frank; Waszak, Sebastian M; Larsen, Martin R; Colino-Sanguino, Yolanda; Valdés-Mora, Fatima; Rakotomalala, Andria; Meignan, Samuel; Pasquier, Eddy; Andre, Nicolas; Hulleman, Esther; Eisenstat, David D; Vitanza, Nicholas A; Nazarian, Javad; Koschmann, Carl; Mueller, Sabine; Cain, Jason E; Dun, Matthew D.
Afiliação
  • Jackson ER; The University of Newcastle, Callaghan, NSW, Australia.
  • Duchatel RJ; The University of Newcastle, Callaghan, NSW, Australia.
  • Staudt DE; The University of Newcastle, Callaghan, NSW, Australia.
  • Persson ML; The University of Newcastle, Callaghan, NSW, Australia.
  • Mannan A; The University of Newcastle, Callaghan, NSW, Australia.
  • Yadavilli S; Children's National Hospital, Washington, DC, United States.
  • Parackal S; Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Game S; Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Chong WC; Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Jayasekara WSN; Hudson Institute of Medical Research, Clayton, Victoria, Australia.
  • Le Grand M; Cancer Research Center of Marseille, Marseille CEDEX 09, France.
  • Kearney PS; The University of Newcastle, Callaghan, NSW, Australia.
  • Douglas AM; The University of Newcastle, Callaghan, NSW, Australia.
  • Findlay IJ; The University of Newcastle, Callaghan, NSW, Australia.
  • Germon ZP; The University of Newcastle, Callaghan, NSW, Australia.
  • McEwen HP; The University of Newcastle, Callaghan, NSW, Australia.
  • Beitaki TS; The University of Newcastle, Callaghan, NSW, Australia.
  • Patabendige A; Edge Hill University, Ormskirk, United Kingdom.
  • Skerrett-Byrne DA; The University of Newcastle, Callaghan, NSW, Australia.
  • Nixon B; The University of Newcastle, Callaghan, NSW, Australia.
  • Smith ND; The University of Newcastle, Callaghan, NSW, Australia.
  • Day B; QIMR Berghofer MRI, Brisbane, Queensland, Australia.
  • Manoharan N; Sydney Children's Hospital, Randwick, NSW, Australia.
  • Nagabushan S; Sydney Children's Hospital, Randwick, New South Wales, Australia.
  • Hansford JR; Women's and Children's Hospital, North Adelaide, SA, Australia.
  • Govender D; The Children's Hospital at Westmead, Westmead, NSW, Australia.
  • McCowage GB; Children's Hospital at Westmead, Sydney, Australia.
  • Firestein R; Genentech Inc, S. San Francisco, United States.
  • Howlett M; University of Western Australia, Perth, WA, Australia.
  • Endersby R; Telethon Kids Institute, Nedlands, Western Australia, Australia.
  • Gottardo NG; Telethon Kids Institute, Perth, Western Australia, Australia.
  • Alvaro F; John Hunter Children's Hospital, New Lambton Heights, NSW, Australia.
  • Waszak SM; University of Oslo, Oslo, Norway.
  • Larsen MR; University of Southern Denmark, Odense M, Denmark.
  • Colino-Sanguino Y; Children's Cancer Institute, Sydney, NSW, Australia.
  • Valdés-Mora F; Children's Cancer Institute, Sydney, Australia.
  • Rakotomalala A; Univ. Lille, CNRS, Inserm, CHU Lille, Centre Oscar Lambret, Lille, France.
  • Meignan S; Centre Oscar Lambret, LILLE, France.
  • Pasquier E; Cancer Research Center of Marseille, Marseille CEDEX 09, France.
  • Andre N; AP-HM, Aix Marseille Université, Marseille, France.
  • Hulleman E; VU University Medical Center-Cancer Centrer Amsterdam, Amsterdam, Netherlands.
  • Eisenstat DD; The Royal Children's Hospital and University of Melbourne, Melbourne, Victoria, Australia.
  • Vitanza NA; Seattle Children's Research Institute, Seattle, WA, United States.
  • Nazarian J; Children's National Medical Center, Washington, United States.
  • Koschmann C; University of Michigan-Ann Arbor, Ann Arbor, MI, United States.
  • Mueller S; University of California, San Francisco, San Francisco, CA, United States.
  • Cain JE; Hudson Institute of Medical Research, Clayton, Victoria, Australia.
  • Dun MD; The University of Newcastle, Callaghan, NSW, Australia.
Cancer Res ; 2023 May 05.
Article em En | MEDLINE | ID: mdl-37145169
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 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, while 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Cancer Res Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Austrália
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Cancer Res Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Austrália