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dc.contributor.authorSkwarski, M
dc.contributor.authorMcGowan, DR
dc.contributor.authorBelcher, E
dc.contributor.authorDi Chiara, F
dc.contributor.authorStavroulias, D
dc.contributor.authorMcCole, M
dc.contributor.authorDerham, JL
dc.contributor.authorChu, K-Y
dc.contributor.authorTeoh, E
dc.contributor.authorChauhan, J
dc.contributor.authorO'Reilly, D
dc.contributor.authorHarris, BHL
dc.contributor.authorMacklin, PS
dc.contributor.authorBull, JA
dc.contributor.authorGreen, M
dc.contributor.authorRodriguez-Berriguete, G
dc.contributor.authorPrevo, R
dc.contributor.authorFolkes, LK
dc.contributor.authorCampo, L
dc.contributor.authorFerencz, P
dc.contributor.authorCroal, PL
dc.contributor.authorFlight, H
dc.contributor.authorQi, C
dc.contributor.authorHolmes, J
dc.contributor.authorO'Connor, JPB
dc.contributor.authorGleeson, FV
dc.contributor.authorMcKenna, WG
dc.contributor.authorHarris, AL
dc.contributor.authorBulte, D
dc.contributor.authorBuffa, FM
dc.contributor.authorMacpherson, RE
dc.contributor.authorHiggins, GS
dc.date.accessioned2021-03-31T14:45:55Z
dc.date.available2021-03-31T14:45:55Z
dc.date.issued2021-02-17
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2021
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4486
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-20-4128
dc.description.abstractPurpose Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC).Patients and methods Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed.Results Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 ( P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported.Conclusions This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.titleMitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer.
dc.typeJournal Article
dcterms.dateAccepted2021-02-11
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/1078-0432.ccr-20-4128
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2021-02-17
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.notesNot known
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/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Quantitative Biomedical Imaging
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/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Quantitative Biomedical Imaging
pubs.publication-statusPublished
pubs.embargo.termsNot known
icr.researchteamQuantitative Biomedical Imaging
icr.researchteamQuantitative Biomedical Imagingen_US
dc.contributor.icrauthorO'Connor, James Patricken


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