Proteomics

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ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

ABSTRACT: Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Cell Culture

DISEASE(S): Diffuse Midline Glioma

SUBMITTER: Zac Germon  

LAB HEAD: Matt Dun

PROVIDER: PXD036245 | Pride | 2023-05-25

REPOSITORIES: Pride

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Dataset's files

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DIPG6_EXP3_00989_MLP.raw Raw
DIPG6_EXP3_00990_MLP.raw Raw
DIPG6_EXP3_00991_MLP.raw Raw
DIPG6_EXP3_00992_MLP.raw Raw
DIPG6_EXP3_00993_MLP.raw Raw
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Publications

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

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

Cancer research 20230517

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 influ  ...[more]

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