Ang, Joo ErnPandher, RupinderAng, Joo ChewAsad, Yasmin JHenley, Alan TValenti, MelanieBox, Garyde, Haven Brandon AlexisBaird, RichardFriedman, LoriDerynck, MikaVanhaesebroeck, BartEccles, Suzanne AKaye, Stan BWorkman, Paulde, Bono Johann SRaynaud, Florence IAntwerp X-ray Analysis, Electrochemistry and Speciation (AXES)2019-04-262019-04-2605/04/16https://dspace7-entities.atmire.com/handle/atmire/449PI3K 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.