Chen, Jingwei, Nelson, Christopher, Wong, Matthew ORCID: 0000-0003-2680-961X, Tee, Andrew E., Liu, Pei Y., La, Ting ORCID: 0000-0001-6072-5722, Fletcher, Jamie I., Kamili, Alvin ORCID: 0000-0002-4864-1195, Mayoh, Chelsea ORCID: 0000-0002-6398-3046, Bartenhagen, Christoph, Trahair, Toby N., Xu, Ning, Jayatilleke, Nisitha, Wong, Marie, Peng, Hui, Atmadibrata, Bernard, Cheung, Belamy B., Lan, Qing, Bryan, Tracy M., Mestdagh, Pieter ORCID: 0000-0001-7821-9684, Vandesompele, Jo ORCID: 0000-0001-6274-0184, Combaret, Valerie, Boeva, Valentina, Wang, Jenny Y. ORCID: 0000-0002-1325-7943, Janoueix-Lerosey, Isabelle, Cowley, Mark J., MacKenzie, Karen L., Dolnikov, Alla, Li, Jinyan, Polly, Patsie, Marshall, Glenn M., Reddel, Roger R., Norris, Murray D., Haber, Michelle, Fischer, Matthias, Zhang, Xu D., Pickett, Hilda A. and Liu, Tao ORCID: 0000-0001-6244-7316 (2021). Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy. Clin. Cancer Res., 27 (5). S. 1438 - 1452. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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Abstract

Purpose: TERT gene rearrangement with transcriptional super-enhancers 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Chen, JingweiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nelson, ChristopherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wong, MatthewUNSPECIFIEDorcid.org/0000-0003-2680-961XUNSPECIFIED
Tee, Andrew E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, Pei Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
La, TingUNSPECIFIEDorcid.org/0000-0001-6072-5722UNSPECIFIED
Fletcher, Jamie I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kamili, AlvinUNSPECIFIEDorcid.org/0000-0002-4864-1195UNSPECIFIED
Mayoh, ChelseaUNSPECIFIEDorcid.org/0000-0002-6398-3046UNSPECIFIED
Bartenhagen, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trahair, Toby N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xu, NingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jayatilleke, NisithaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wong, MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peng, HuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Atmadibrata, BernardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheung, Belamy B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lan, QingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bryan, Tracy M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mestdagh, PieterUNSPECIFIEDorcid.org/0000-0001-7821-9684UNSPECIFIED
Vandesompele, JoUNSPECIFIEDorcid.org/0000-0001-6274-0184UNSPECIFIED
Combaret, ValerieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boeva, ValentinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, Jenny Y.UNSPECIFIEDorcid.org/0000-0002-1325-7943UNSPECIFIED
Janoueix-Lerosey, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cowley, Mark J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacKenzie, Karen L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dolnikov, AllaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, JinyanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polly, PatsieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marshall, Glenn M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reddel, Roger R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Norris, Murray D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haber, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, Xu D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pickett, Hilda A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, TaoUNSPECIFIEDorcid.org/0000-0001-6244-7316UNSPECIFIED
URN: urn:nbn:de:hbz:38-605253
DOI: 10.1158/1078-0432.CCR-20-3044
Journal or Publication Title: Clin. Cancer Res.
Volume: 27
Number: 5
Page Range: S. 1438 - 1452
Date: 2021
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SELECTIVE-INHIBITION; MULTIPLE-MYELOMA; DOSE-ESCALATION; ACUTE-LEUKEMIA; OPEN-LABEL; PHASE-II; TELOMERASE; BORTEZOMIB; OTX015; MYCMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60525

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