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Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.

Accepted version
Peer-reviewed

Type

Article

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Authors

Ang, Joo Ern 
Pandher, Rupinder 
Ang, Joo Chew 
Asad, Yasmin J 
Henley, Alan T 

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.

Description

Keywords

Animals, Biomarkers, Tumor, Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Indazoles, Mass Spectrometry, Metabolome, Metabolomics, Mice, Neoplasm Transplantation, Neoplasms, PTEN Phosphohydrolase, Sulfonamides, Time Factors

Journal Title

Mol Cancer Ther

Conference Name

Journal ISSN

1535-7163
1538-8514

Volume Title

Publisher

American Association for Cancer Research (AACR)
Sponsorship
The Institute of Cancer Research