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dc.contributor.author
Chen, Jingwei
dc.contributor.author
Boeva, Valentina
dc.contributor.author
et al.
dc.date.accessioned
2021-03-24T08:25:54Z
dc.date.available
2021-03-18T04:38:42Z
dc.date.available
2021-03-24T08:25:54Z
dc.date.issued
2021-03
dc.identifier.issn
1078-0432
dc.identifier.issn
1557-3265
dc.identifier.other
10.1158/1078-0432.CCR-20-3044
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/475210
dc.description.abstract
Purpose: TERT gene rearrangement with transcriptional superenhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma. Experimental Design: Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. Results: The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. Conclusions: OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma. © 2020 American Association for Cancer Research
en_US
dc.language.iso
en
en_US
dc.publisher
American Association for Cancer Research
en_US
dc.title
Targeted therapy of TERT-rearranged neuroblastoma with BET bromodomain inhibitor and proteasome inhibitor combination therapy
en_US
dc.type
Journal Article
dc.date.published
2020-12-11
ethz.journal.title
Clinical Cancer Research
ethz.journal.volume
27
en_US
ethz.journal.issue
5
en_US
ethz.journal.abbreviated
Clin Cancer Res
ethz.pages.start
1438
en_US
ethz.pages.end
1451
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Philadelphia, PA
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02150 - Dep. Informatik / Dep. of Computer Science::02661 - Institut für Maschinelles Lernen / Institute for Machine Learning::09671 - Boeva, Valentina / Boeva, Valentina
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02150 - Dep. Informatik / Dep. of Computer Science::02661 - Institut für Maschinelles Lernen / Institute for Machine Learning::09671 - Boeva, Valentina / Boeva, Valentina
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02150 - Dep. Informatik / Dep. of Computer Science::02661 - Institut für Maschinelles Lernen / Institute for Machine Learning::09671 - Boeva, Valentina / Boeva, Valentina
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02150 - Dep. Informatik / Dep. of Computer Science::02661 - Institut für Maschinelles Lernen / Institute for Machine Learning::09671 - Boeva, Valentina / Boeva, Valentina
ethz.date.deposited
2021-03-18T04:38:53Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2021-03-24T08:26:16Z
ethz.rosetta.lastUpdated
2023-02-06T21:38:01Z
ethz.rosetta.versionExported
true
ethz.COinS
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