Publication:
Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation

dc.contributor.author Ang, Joo Ern
dc.contributor.author Pandher, Rupinder
dc.contributor.author Ang, Joo Chew
dc.contributor.author Asad, Yasmin J
dc.contributor.author Henley, Alan T
dc.contributor.author Valenti, Melanie
dc.contributor.author Box, Gary
dc.contributor.author de, Haven Brandon Alexis
dc.contributor.author Baird, Richard
dc.contributor.author Friedman, Lori
dc.contributor.author Derynck, Mika
dc.contributor.author Vanhaesebroeck, Bart
dc.contributor.author Eccles, Suzanne A
dc.contributor.author Kaye, Stan B
dc.contributor.author Workman, Paul
dc.contributor.author de, Bono Johann S
dc.contributor.author Raynaud, Florence I
dc.contributor.other Antwerp X-ray Analysis, Electrochemistry and Speciation (AXES)
dc.date.accessioned 2019-04-26T08:57:05Z
dc.date.available 2019-04-26T08:57:05Z
dc.date.issued 05/04/16
dc.description PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometryΓÇôbased metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with nonΓÇôtumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a phase I dose-escalation clinical trial of pictilisib. Time- and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition.
dc.identifier.uri https://demo7.dspace.org/handle/10673/449
dc.language en
dc.publisher American Association for Cancer Research
dc.title Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation
dspace.entity.type Publication
relation.isAuthorOfPublication 9deca3f8-9c0c-4050-8cc3-f0f6132dbd6e
relation.isOrgUnitOfPublication f74aac80-2004-412a-9a88-838c5944395b
relation.isProjectOfPublication 101341ff-36df-4d0f-bc65-5ad503e87f6e
relation.isProjectOfPublication 3329a278-2719-4bae-a5d5-d2039afc2fe2
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