dc.contributor.author | Romo-Morales, A | |
dc.contributor.author | Aladowicz, E | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Gatz, SA | |
dc.contributor.author | Shipley, JM | |
dc.date.accessioned | 2019-06-20T11:20:42Z | |
dc.date.issued | 2019-09-01 | |
dc.identifier.citation | Pediatric blood & cancer, 2019, 66 (9), pp. e27888 - ? | |
dc.identifier.issn | 1545-5009 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3263 | |
dc.identifier.eissn | 1545-5017 | |
dc.identifier.doi | 10.1002/pbc.27888 | |
dc.description.abstract | BACKGROUND: 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. | |
dc.format | Print-Electronic | |
dc.format.extent | e27888 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | WILEY | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Bone Neoplasms | |
dc.subject | RNA-Binding Protein EWS | |
dc.subject | Oncogene Proteins, Fusion | |
dc.subject | Antineoplastic Agents | |
dc.subject | Enzyme Inhibitors | |
dc.subject | Proto-Oncogene Protein c-fli-1 | |
dc.subject | Histone Demethylases | |
dc.subject | Sarcoma, Ewing | |
dc.title | Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-05-31 | |
rioxxterms.versionofrecord | 10.1002/pbc.27888 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Pediatric blood & cancer | |
pubs.issue | 9 | |
pubs.notes | Not 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/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.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 66 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Sarcoma Molecular Pathology | |
dc.contributor.icrauthor | Romo-Morales, Antonio | |
dc.contributor.icrauthor | Shipley, Janet | |