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dc.contributor.authorNakayama, Roberten_US
dc.contributor.authorZhang, Yi-Xiangen_US
dc.contributor.authorCzaplinski, Jeffrey T.en_US
dc.contributor.authorAnatone, Alex J.en_US
dc.contributor.authorSicinska, Ewa T.en_US
dc.contributor.authorFletcher, Jonathan A.en_US
dc.contributor.authorDemetri, George D.en_US
dc.contributor.authorWagner, Andrew J.en_US
dc.date.accessioned2016-08-09T14:52:42Z
dc.date.issued2016en_US
dc.identifier.citationNakayama, Robert, Yi-Xiang Zhang, Jeffrey T. Czaplinski, Alex J. Anatone, Ewa T. Sicinska, Jonathan A. Fletcher, George D. Demetri, and Andrew J. Wagner. 2016. “Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma.” Oncotarget 7 (13): 16581-16592. doi:10.18632/oncotarget.7667. http://dx.doi.org/10.18632/oncotarget.7667.en
dc.identifier.issn1949-2553en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:27822175
dc.description.abstractSelinexor is an orally bioavailable selective inhibitor of nuclear export that has been demonstrated to have preclinical activity in various cancer types and that is currently in Phase I and II clinical trials for advanced cancers. In this study, we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes. The efficacy of selinexor was investigated in vitro and in vivo using 17 cell lines and 9 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. In GIST cells with KIT mutations, selinexor induced G1- arrest without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines with MDM2 and CDK4 amplification, selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation and irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA level, indicating a post-transcriptional effect. These results indicate that selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models by inducing G1-arrest independent of known molecular mechanisms in GIST and LPS. These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes.en
dc.language.isoen_USen
dc.publisherImpact Journals LLCen
dc.relation.isversionofdoi:10.18632/oncotarget.7667en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941336/pdf/en
dash.licenseLAAen_US
dc.subjectsarcomaen
dc.subjectgastrointestinal stromal tumoren
dc.subjectliposarcomaen
dc.subjectselinexoren
dc.subjectpreclinical studyen
dc.titlePreclinical activity of selinexor, an inhibitor of XPO1, in sarcomaen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalOncotargeten
dash.depositing.authorNakayama, Roberten_US
dc.date.available2016-08-09T14:52:42Z
dc.identifier.doi10.18632/oncotarget.7667*
dash.contributor.affiliatedWagner, Andrew
dash.contributor.affiliatedNakayama, Robert
dash.contributor.affiliatedDemetri, George
dash.contributor.affiliatedFletcher, Jonathan
dash.contributor.affiliatedSicinska, Ewa


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