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dc.contributor.authorPal, A
dc.contributor.authorAsad, Y
dc.contributor.authorRuddle, R
dc.contributor.authorHenley, AT
dc.contributor.authorSwales, K
dc.contributor.authorDecordova, S
dc.contributor.authorEccles, SA
dc.contributor.authorCollins, I
dc.contributor.authorGarrett, MD
dc.contributor.authorDe Bono, J
dc.contributor.authorBanerji, U
dc.contributor.authorRaynaud, FI
dc.date.accessioned2020-04-22T14:45:30Z
dc.date.issued2020-04-13
dc.identifier.citationMetabolomics : Official journal of the Metabolomic Society, 2020, 16 (4), pp. 50 - ?
dc.identifier.issn1573-3882
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3595
dc.identifier.eissn1573-3890
dc.identifier.doi10.1007/s11306-020-01676-0
dc.description.abstractINTRODUCTION: To generate biomarkers of target engagement or predictive response for multi-target drugs is challenging. One such compound is the multi-AGC kinase inhibitor AT13148. Metabolic signatures of selective signal transduction inhibitors identified in preclinical models have previously been confirmed in early clinical studies. This study explores whether metabolic signatures could be used as biomarkers for the multi-AGC kinase inhibitor AT13148. OBJECTIVES: To identify metabolomic changes of biomarkers of multi-AGC kinase inhibitor AT13148 in cells, xenograft / mouse models and in patients in a Phase I clinical study. METHODS: HILIC LC-MS/MS methods and Biocrates AbsoluteIDQ™ p180 kit were used for targeted metabolomics; followed by multivariate data analysis in SIMCA and statistical analysis in Graphpad. Metaboanalyst and String were used for network analysis. RESULTS: BT474 and PC3 cells treated with AT13148 affected metabolites which are in a gene protein metabolite network associated with Nitric oxide synthases (NOS). In mice bearing the human tumour xenografts BT474 and PC3, AT13148 treatment did not produce a common robust tumour specific metabolite change. However, AT13148 treatment of non-tumour bearing mice revealed 45 metabolites that were different from non-treated mice. These changes were also observed in patients at doses where biomarker modulation was observed. Further network analysis of these metabolites indicated enrichment for genes associated with the NOS pathway. The impact of AT13148 on the metabolite changes and the involvement of NOS-AT13148- Asymmetric dimethylarginine (ADMA) interaction were consistent with hypotension observed in patients in higher dose cohorts (160-300 mg). CONCLUSION: AT13148 affects metabolites associated with NOS in cells, mice and patients which is consistent with the clinical dose-limiting hypotension.
dc.formatElectronic
dc.format.extent50 - ?
dc.languageeng
dc.language.isoeng
dc.publisherSPRINGER
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleMetabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation.
dc.typeJournal Article
dcterms.dateAccepted2020-04-03
rioxxterms.versionofrecord10.1007/s11306-020-01676-0
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-04-13
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMetabolomics : Official journal of the Metabolomic Society
pubs.issue4
pubs.notesNo embargo
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/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
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/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.publication-statusPublished
pubs.volume16
pubs.embargo.termsNo embargo
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
icr.researchteamMedicinal Chemistry 2
icr.researchteamClinical Pharmacology – Adaptive Therapy
icr.researchteamProstate Cancer Targeted Therapy Group
dc.contributor.icrauthorPal, Akos
dc.contributor.icrauthorRuddle, Ruth
dc.contributor.icrauthorSwales, Karen
dc.contributor.icrauthorCollins, Ian
dc.contributor.icrauthorDe Bono, Johann
dc.contributor.icrauthorBanerji, Udai
dc.contributor.icrauthorRaynaud, Florence


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