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 Nilanthi 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 NixonNathan D Smith, Bryan Day, Neevika Manoharan, Sumanth Nagabushan, Jordan R Hansford, Dinisha Govender, Geoffrey B McCowage, Ron Firestein, Meegan Howlett, Raelene Endersby, Nicholas G Gottardo, Frank Alvaro, Sebastian M Waszak, Martin R Larsen, Yolanda Colino-Sanguino, Fatima Valdés-Mora, Andria Rakotomalala, Samuel Meignan, Eddy Pasquier, Nicolas Andre, Esther Hulleman, David D Eisenstat, Nicholas A Vitanza, Javad Nazarian, Carl Koschmann, Sabine Mueller, Jason E Cain, Matthew D Dun

Research output: Contribution to journalArticle (journal)peer-review

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1-17
JournalCancer Research
Early online date5 May 2023
DOIs
Publication statusPublished - 17 May 2023

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