ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma
Date
2023
Authors
Jackson, E.R.
Duchatel, R.J.
Staudt, D.E.
Persson, M.L.
Mannan, A.
Yadavilli, S.
Parackal, S.
Game, S.
Chong, W.C.
Jayasekara, W.S.N.
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Advisors
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Journal article
Citation
Cancer Research, 2023; 83(14):2421-2437
Statement of Responsibility
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 Andr, e, Esther Hulleman, David D. Eisenstat, Nicholas A. Vitanza, Javad Nazarian, Carl Koschmann, Sabine Mueller, Jason E. Cain, and Matthew D. Dun
Conference Name
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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© 2023 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under the Creative Commons Attribution- NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.