Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.
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Date
2016-06-01Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
Animals
Humans
Mice
Neoplasms
Sulfonamides
Indazoles
Neoplasm Transplantation
Dose-Response Relationship, Drug
Time Factors
PTEN Phosphohydrolase
Mass Spectrometry
Metabolomics
Metabolome
Biomarkers, Tumor
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Prostate Cancer Targeted Therapy Group
Medicine Drug Development Unit (Kaye)
Language
eng
Date accepted
2016-03-29
License start date
2016-06
Citation
Molecular cancer therapeutics, 2016, 15 (6), pp. 1412 - 1424
Publisher
AMER ASSOC CANCER RESEARCH