PI3K 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. Mol Cancer Ther; 
15(6); 1412-24. ©2016 AACR.