Targeted Therapy of <i>TERT</i>-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy.

Chen, J; Nelson, C; Wong, M; Tee, AE; Liu, PY; La, T; Fletcher, JI; Kamili, A; Mayoh, C; Bartenhagen, C; Trahair, TN; Xu, N; Jayatilleke, N; Wong, M; Peng, H; Atmadibrata, B; Cheung, BB; Lan, Q; Bryan, TM; Mestdagh, P; Vandesompele, J; Combaret, V; Boeva, V; Wang, JY; Janoueix-Lerosey, I; Cowley, MJ; MacKenzie, KL; Dolnikov, A; Li, J; Polly, P; Marshall, GM; Reddel, RR; Norris, MD; Haber, M; Fischer, M; Zhang, XD; Pickett, HA; Liu, T

Targeted Therapy of <i>TERT</i>-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy.

Chen, J Nelson, C Wong, M Tee, AE Liu, PY La, T Fletcher, JI Kamili, A Mayoh, C Bartenhagen, C Trahair, TN Xu, N Jayatilleke, N Wong, M Peng, H Atmadibrata, B Cheung, BB Lan, Q Bryan, TM Mestdagh, P Vandesompele, J Combaret, V Boeva, V Wang, JY Janoueix-Lerosey, I Cowley, MJ MacKenzie, KL Dolnikov, A Li, J

Polly, P Marshall, GM Reddel, RR Norris, MD Haber, M Fischer, M Zhang, XD Pickett, HA Liu, T

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Publisher:: American Association for Cancer Research (AACR)
Publication Type:: Journal Article
Citation:: Clinical cancer research : an official journal of the American Association for Cancer Research, 2021, 27, (5), pp. 1438-1451
Issue Date:: 2021-03

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Field	Value	Language
dc.contributor.author	Chen, J
dc.contributor.author	Nelson, C
dc.contributor.author	Wong, M
dc.contributor.author	Tee, AE
dc.contributor.author	Liu, PY
dc.contributor.author	La, T
dc.contributor.author	Fletcher, JI
dc.contributor.author	Kamili, A
dc.contributor.author	Mayoh, C
dc.contributor.author	Bartenhagen, C
dc.contributor.author	Trahair, TN
dc.contributor.author	Xu, N
dc.contributor.author	Jayatilleke, N
dc.contributor.author	Wong, M
dc.contributor.author	Peng, H
dc.contributor.author	Atmadibrata, B
dc.contributor.author	Cheung, BB
dc.contributor.author	Lan, Q
dc.contributor.author	Bryan, TM
dc.contributor.author	Mestdagh, P
dc.contributor.author	Vandesompele, J
dc.contributor.author	Combaret, V
dc.contributor.author	Boeva, V
dc.contributor.author	Wang, JY
dc.contributor.author	Janoueix-Lerosey, I
dc.contributor.author	Cowley, MJ
dc.contributor.author	MacKenzie, KL
dc.contributor.author	Dolnikov, A
dc.contributor.author	Li, J https://orcid.org/0000-0003-1833-7413
dc.contributor.author	Polly, P
dc.contributor.author	Marshall, GM
dc.contributor.author	Reddel, RR
dc.contributor.author	Norris, MD
dc.contributor.author	Haber, M
dc.contributor.author	Fischer, M
dc.contributor.author	Zhang, XD
dc.contributor.author	Pickett, HA
dc.contributor.author	Liu, T
dc.date.accessioned	2021-04-26T04:54:34Z
dc.date.available	2020-12-08
dc.date.available	2021-04-26T04:54:34Z
dc.date.issued	2021-03
dc.identifier.citation	Clinical cancer research : an official journal of the American Association for Cancer Research, 2021, 27, (5), pp. 1438-1451
dc.identifier.issn	1078-0432
dc.identifier.issn	1557-3265
dc.identifier.uri	http://hdl.handle.net/10453/148374
dc.description.abstract	<h4>Purpose</h4><i>TERT</i> gene rearrangement with transcriptional superenhancers leads to <i>TERT</i> overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with <i>TERT</i>-rearranged neuroblastoma.<h4>Experimental design</h4>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 <i>TERT</i>-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.<h4>Results</h4>The BET bromodomain protein BRD4 promoted <i>TERT</i>-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 <i>TERT</i>-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with <i>TERT</i>-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.<h4>Conclusions</h4>OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with <i>TERT</i>-rearranged neuroblastoma.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	American Association for Cancer Research (AACR)
dc.relation	http://purl.org/au-research/grants/arc/DP180100120
dc.relation.ispartof	Clinical cancer research : an official journal of the American Association for Cancer Research
dc.relation.isbasedon	10.1158/1078-0432.ccr-20-3044
dc.rights	info:eu-repo/semantics/embargoedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.title	Targeted Therapy of <i>TERT</i>-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy.
dc.type	Journal Article
utslib.citation.volume	27
utslib.location.activity	United States
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/A/DRsch The Data Science Institute
utslib.copyright.status	open_access	*
utslib.copyright.embargo	2022-03-01T00:00:00+1000Z
dc.date.updated	2021-04-26T04:54:33Z
pubs.issue	5
pubs.publication-status	Published
pubs.volume	27
utslib.citation.issue	5

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.

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http://hdl.handle.net/10453/148374