PXD036245

PXD036245 is an original dataset announced via ProteomeXchange.

Title	ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma
Description	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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:48:18.391.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zac Germon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-23 05:28:35	ID requested
1	2023-05-24 16:56:06	announced
⏵ 2	2023-11-14 08:48:19	announced	2023-11-14: Updated project metadata.

Jackson ER, Duchatel RJ, Staudt DE, Persson ML, Mannan A, Yadavilli S, Parackal S, Game S, Chong WC, Jayasekara WSN, Grand ML, Kearney PS, Douglas AM, Findlay IJ, Germon ZP, McEwen HP, Beitaki TS, Patabendige A, Skerrett-Byrne DA, Nixon B, Smith ND, Day B, Manoharan N, Nagabushan S, Hansford JR, Govender D, McCowage GB, Firestein R, Howlett M, Endersby R, Gottardo NG, Alvaro F, Waszak SM, Larsen MR, Colino-Sanguino Y, Valdes-Mora F, Rakotomalala A, Meignan S, Pasquier E, Andr, é N, Hulleman E, Eisenstat DD, Vitanza NA, Nazarian J, Koschmann C, Mueller S, Cain JE, Dun MD, ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma. Cancer Res, ():OF1-OF17(2023) [pubmed]

submitter keyword: DMG, CLPP agonist, Targeted therapies,DIPG, ONC201

Matt Dun
contact affiliation	1. Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, AUSTRALIA 2. Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, AUSTRALIA 3. Paediatric Program, Mark Hughes Foundation Centre for Brain Cancer Research, College of Health, Medicine, and Wellbeing, Callaghan, NSW, AUSTRALIA
contact email	matt.dun@newcastle.edu.au
lab head
Zac Germon
contact affiliation	University of Newcastle
contact email	zacary.germon@uon.edu.au
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/05/PXD036245

PRIDE project URI

• PRIDE
  1. PXD036245
     1. Label: PRIDE project
     2. Name: ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma