Journal
MOLECULAR CANCER THERAPEUTICS
Volume 15, Issue 6, Pages 1412-1424Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-15-0815
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Funding
- Cancer Research UK programme grant at the Cancer Research UK Cancer Therapeutics Unit [C309/A11566]
- Wellcome Trust [090952/Z/09/Z]
- Institute of Cancer Research
- Genentech Inc.
- Drug Development Unit
- Royal Marsden NHS Foundation Trust
- Experimental Cancer Medicine Centre
- National Health Service
- Royal Marsden Hospital
- Cancer Research UK [C2338/A15965]
- Wellcome Trust [090952/Z/09/Z] Funding Source: Wellcome Trust
- Cancer Research UK [15965, 11566] Funding Source: researchfish
- Medical Research Council [G0502133] Funding Source: researchfish
- BBSRC [BB/I019405/1] Funding Source: UKRI
- MRC [G0502133] Funding Source: UKRI
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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.
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