Publication:
Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation
Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation
No Thumbnail Available
Date
05/04/16
Authors
Ang, Joo Ern
Pandher, Rupinder
Ang, Joo Chew
Asad, Yasmin J
Henley, Alan T
Valenti, Melanie
Box, Gary
de, Haven Brandon Alexis
Friedman, Lori
Journal Title
Journal ISSN
Volume Title
Publisher
American Association for Cancer Research
Research Projects
Organizational Units
Organizational Unit
Journal Issue
Abstract
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.