Authors:
JE Ang, R Pandher, JC Ang, YJ Asad, AT Henley, M Valenti, G Box, A de Haven Brandon, RD Baird, L Friedman, M Derynck, B Vanhaesebroeck, SA Eccles, SB Kaye, P Workman, JS de Bono, FI Raynaud
Journal name: 
Mol Cancer Ther
Citation info: 
15(6):1412-1424
Abstract: 
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.
DOI: 
http://doi.org/10.1158/1535-7163.MCT-15-0815
E-pub date: 
01 Jun 2016