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

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Raynaud Mol Canc Ther.pdf (1.64 MB)

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ICR Authors

Workman, Paul
 De Bono, Johann
 Raynaud, Florence

Authors

Ang, JE
Pandher, R
Ang, JC
Asad, YJ
Henley, AT
Valenti, M
Box, G
de Haven Brandon, A
Baird, RD
Friedman, L
Derynck, M
Vanhaesebroeck, B
Eccles, SA
Kaye, SB
Workman, P
de Bono, JS
Raynaud, FI

Document Type

Journal Article

Date

2016-06-01

Date Accepted

2016-03-29

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.

Citation

Molecular cancer therapeutics, 2016, 15 (6), pp. 1412 - 1424

DOI

10.1158/1535-7163.mct-15-0815

URI

https://repository.icr.ac.uk/handle/internal/312

Rights

Source Title

Publisher

AMER ASSOC CANCER RESEARCH

ISSN

1535-7163

eISSN

1538-8514

Collections

Cancer Therapeutics
Clinical Studies
Closed Research Teams

Research Team

Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Prostate Cancer Targeted Therapy Group
Medicine Drug Development Unit (Kaye)

Notes