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dc.contributor.authorRomo-Morales, Aen_US
dc.contributor.authorAladowicz, Een_US
dc.contributor.authorBlagg, Jen_US
dc.contributor.authorGatz, SAen_US
dc.contributor.authorShipley, JMen_US
dc.date.accessioned2019-06-20T11:20:42Z
dc.date.issued2019-09en_US
dc.identifier.citationPediatric blood & cancer, 2019, 66 (9), pp. e27888 - ?en_US
dc.identifier.issn1545-5009en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3263
dc.identifier.eissn1545-5017en_US
dc.identifier.doi10.1002/pbc.27888en_US
dc.description.abstractBACKGROUND:Ewing sarcoma and desmoplastic small round cell tumors (DSRCT) are rare and clinically aggressive sarcomas usually characterized by oncogenic fusion proteins involving EWS. Emerging studies of Ewing sarcoma have demonstrated EWS-FLI1-driven chromatin remodeling as a key aspect of tumorigenicity. In particular, the lysine-specific demethylase KDM1A/LSD1 is linked to transcriptional regulation of target genes orchestrated by the EWS portion of the fusion protein interacting with repressive chromatin-remodeling complexes. Consistent with this model, depletion of KDM1A supports it is a molecular therapeutic target in Ewing sarcoma cells, but effective drugs need to be identified. PROCEDURE:A comprehensive phenotypic analysis of the effects of catalytic KDM1A inhibitors ORY-1001 and GSK2879552, including clinically relevant doses, was carried out in 2D and 3D spheroid models of Ewing sarcoma and DSRCT. RESULTS:Catalytic inhibition of KDM1A did not affect cell viability in 2D and 3D assays and had no impact on invasion in a 3D assay. CONCLUSIONS:Overall, evidence presented here does not support inhibition of KDM1A catalytic demethylase activity as an effective therapeutic strategy for Ewing sarcoma or DSRCT. However, roles of KDM1A beyond its demethylase activity should be considered for these sarcomas.en_US
dc.formatPrint-Electronicen_US
dc.format.extente27888 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCell Line, Tumoren_US
dc.subjectHumansen_US
dc.subjectBone Neoplasmsen_US
dc.subjectRNA-Binding Protein EWSen_US
dc.subjectOncogene Proteins, Fusionen_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectEnzyme Inhibitorsen_US
dc.subjectProto-Oncogene Protein c-fli-1en_US
dc.subjectHistone Demethylasesen_US
dc.subjectSarcoma, Ewingen_US
dc.titleCatalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-05-31en_US
rioxxterms.versionofrecord10.1002/pbc.27888en_US
rioxxterms.licenseref.startdate2019-09en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfPediatric blood & canceren_US
pubs.issue9en_US
pubs.notesNot knownen_US
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/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology
pubs.publication-statusPublisheden_US
pubs.volume66en_US
pubs.embargo.termsNot knownen_US
icr.researchteamSarcoma Molecular Pathologyen_US
dc.contributor.icrauthorRomo-Morales, Antonioen_US
dc.contributor.icrauthorShipley, Janeten_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/