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Plasma metabolomic changes following PI3K inhibition as pharmacodynamic biomarkers: preclinical discovery to Phase I trial evaluation

Ang, JE; Pandher, R; Ang, JC; Asad, YJ; Henley, A; Valenti, M; Box, G; ... Raynaud, FI; + view all (2016) Plasma metabolomic changes following PI3K inhibition as pharmacodynamic biomarkers: preclinical discovery to Phase I trial evaluation. Molecular Cancer Therapeutics , 15 (6) pp. 1412-1424. 10.1158/1535-7163.MCT-15-0815. Green open access

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Abstract

Phosphoinositide-3-kinase (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.

Type: Article
Title: Plasma metabolomic changes following PI3K inhibition as pharmacodynamic biomarkers: preclinical discovery to Phase I trial evaluation
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/1535-7163.MCT-15-0815
Publisher version: http://dx.doi.org/10.1158/1535-7163.MCT-15-0815
Language: English
Additional information: Copyright © 2016 American Association for Cancer Research.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/1481561
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