PXD036114

PXD036114 is an original dataset announced via ProteomeXchange.

Title	Preclinical Optimization of the PI3K/Akt inhibitor Paxalisib for the Treatment of Diffuse Midline Glioma
Description	Diffuse midline glioma (DMG) is a uniformly fatal pediatric, adolescent, and young adult cancer diagnosed in the midline structures of the brain. PI3K/Akt signaling is an overarching contributor to the poor outcomes of DMG patients due to their dependance on insulin and recurring mutations and amplifications in PI3K/Akt genes. Paxalisib (GDC-0084) is a potent PI3K/Akt inhibitor developed to penetrate the brain’s protective blood-brain barrier (BBB). We performed paxalisib regimen optimization by assessment of blood glucose levels, analysis in vivo pharmacokinetics/pharmacodynamics properties, and employed DMG patient derived xenograft (PDX) mouse models to determine preclinical efficacy. To identify novel combination strategies, we conducted high-resolution quantitative phosphoproteomics of DMG cells treated with paxalisib. Elevated blood glucose levels promoting hyperglycemia was seen in mice using paxalisib 10 mg/kg/day (~mouse equivalent human maximum tolerated dose- NCT03696355). Whereas 5 mg/kg/day, or 5mg/kg/b.i.d. (twice daily) non-significantly increased blood glucose levels compared to controls. Pharmacokinetic analysis of mouse tissues showed 5 mg/kg/b.i.d. increased paxalisib acumination in the brainstem, suppressing PI3K/Akt signaling to significantly extend the survival of DMG PDX models compared to all other regimens; a survival benefit amplified when combined with the anti-glycemic therapy metformin. Phosphoproteomic profiling identified increased Protein kinase C (PKC) signaling following paxalisib treatment. The combination of paxalisib and enzastaurin (PKC inhibitor) synergistically extended the survival of PDX models. Our optimized dosing regimen increased the preclinical benefits of paxalisib, with the combination of paxalisib with metformin, or paxalisib with enzastaurin, heralding rationally designed combination strategies for the treatment of DMG
HostingRepository	PRIDE
AnnounceDate	2024-02-20
AnnouncementXML	Submission_2024-02-20_14:19:32.822.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
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-16 13:59:20	ID requested
⏵ 1	2024-02-20 14:19:33	announced

10.1172/JCI170329;

submitter keyword: Phosphoproteomics, DMG, Proteogenomics,DIPG, PI3K/AKT, Paxalisib

Matthew Dun
contact affiliation	Cancer Signalling Research Group, School of Biomedical Science and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, AUSTRALIA. Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, 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

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PRIDE project URI

• PRIDE
  1. PXD036114
     1. Label: PRIDE project
     2. Name: Preclinical Optimization of the PI3K/Akt inhibitor Paxalisib for the Treatment of Diffuse Midline Glioma