Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation
Ang, Joo Ern Pandher, Rupinder Ang, Joo Chew Asad, Yasmin J Henley, Alan T Valenti, Melanie Box, Gary de, Haven Brandon Alexis Baird, Richard Friedman, Lori
Ang, Joo Ern
Pandher, Rupinder
Ang, Joo Chew
Asad, Yasmin J
Henley, Alan T
Valenti, Melanie
Box, Gary
de, Haven Brandon Alexis
Friedman, Lori
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Abstract
Description
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.
Date
05/04/16
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Publisher
American Association for Cancer Research
