dc.contributor.author | Ang, JE | |
dc.contributor.author | Pandher, R | |
dc.contributor.author | Ang, JC | |
dc.contributor.author | Asad, YJ | |
dc.contributor.author | Henley, AT | |
dc.contributor.author | Valenti, M | |
dc.contributor.author | Box, G | |
dc.contributor.author | de Haven Brandon, A | |
dc.contributor.author | Baird, RD | |
dc.contributor.author | Friedman, L | |
dc.contributor.author | Derynck, M | |
dc.contributor.author | Vanhaesebroeck, B | |
dc.contributor.author | Eccles, SA | |
dc.contributor.author | Kaye, SB | |
dc.contributor.author | Workman, P | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | Raynaud, FI | |
dc.date.accessioned | 2016-11-25T10:27:50Z | |
dc.date.issued | 2016-06-01 | |
dc.identifier.citation | Molecular cancer therapeutics, 2016, 15 (6), pp. 1412 - 1424 | |
dc.identifier.issn | 1535-7163 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/312 | |
dc.identifier.eissn | 1538-8514 | |
dc.identifier.doi | 10.1158/1535-7163.mct-15-0815 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 1412 - 1424 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Neoplasms | |
dc.subject | Sulfonamides | |
dc.subject | Indazoles | |
dc.subject | Neoplasm Transplantation | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Time Factors | |
dc.subject | PTEN Phosphohydrolase | |
dc.subject | Mass Spectrometry | |
dc.subject | Metabolomics | |
dc.subject | Metabolome | |
dc.subject | Biomarkers, Tumor | |
dc.title | Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-03-29 | |
rioxxterms.versionofrecord | 10.1158/1535-7163.mct-15-0815 | |
rioxxterms.licenseref.startdate | 2016-06 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Molecular cancer therapeutics | |
pubs.issue | 6 | |
pubs.notes | 6 months | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Medicine Drug Development Unit (Kaye) | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Medicine Drug Development Unit (Kaye) | |
pubs.publication-status | Published | |
pubs.volume | 15 | |
pubs.embargo.terms | 6 months | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Medicine Drug Development Unit (Kaye) | |
dc.contributor.icrauthor | Workman, Paul | |
dc.contributor.icrauthor | De Bono, Johann | |
dc.contributor.icrauthor | Raynaud, Florence | |