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Mol Cancer Ther. 2016 Jun;15(6):1412-24. doi: 10.1158/1535-7163.MCT-15-0815. Epub 2016 Apr 5.

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

Author information

1
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom. Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
2
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
3
School of Physics, University of Melbourne, Melbourne, Victoria, Australia.
4
Genentech Inc., South San Francisco, California.
5
UCL Cancer Institute, University College London, London, United Kingdom.
6
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom. Drug Development Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom. Florence.Raynaud@icr.ac.uk.

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.

PMID:
27048952
PMCID:
PMC5321508
DOI:
10.1158/1535-7163.MCT-15-0815
[Indexed for MEDLINE]
Free PMC Article

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