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

Simple item page
dc.contributor.authorAng, Joo Ern
dc.contributor.authorPandher, Rupinder
dc.contributor.authorAng, Joo Chew
dc.contributor.authorAsad, Yasmin J
dc.contributor.authorHenley, Alan T
dc.contributor.authorValenti, Melanie
dc.contributor.authorBox, Gary
dc.contributor.authorde, Haven Brandon Alexis
dc.contributor.authorFriedman, Lori
dc.contributor.authorDerynck, Mika
dc.contributor.authorVanhaesebroeck, Bart
dc.contributor.authorEccles, Suzanne A
dc.contributor.authorKaye, Stan B
dc.contributor.authorWorkman, Paul
dc.contributor.authorde, Bono Johann S
dc.contributor.authorRaynaud, Florence I
dc.date.accessioned2019-04-26T08:57:05Z
dc.date.available2019-04-26T08:57:05Z
dc.date.issued05/04/16
dc.descriptionPI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry–based 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 non–tumor-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.urihttps://dspace7-entities.atmire.com/handle/atmire/449
dc.languageen
dc.publisherAmerican Association for Cancer Research
dc.titlePlasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation
Files
Collections
Publications 2