Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma.

Xiao, L; Somers, K; Murray, J; Pandher, R; Karsa, M; Ronca, E; Bongers, A; Terry, R; Ehteda, A; Gamble, LD; Issaeva, N; Leonova, KI; O'Connor, A; Mayoh, C; Venkat, P; Quek, H; Brand, J; Kusuma, FK; Pettitt, JA; Mosmann, E; Kearns, A; Eden, G; Alfred, S; Allan, S; Zhai, L; Kamili, A; Gifford, AJ; Carter, DR; Henderson, MJ; Fletcher, JI; Marshall, G; Johnstone, RW; Cesare, AJ; Ziegler, DS; Gudkov, AV; Gurova, KV; Norris, MD; Haber, M

Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma.

Xiao, L Somers, K Murray, J Pandher, R Karsa, M Ronca, E Bongers, A Terry, R Ehteda, A Gamble, LD Issaeva, N Leonova, KI O'Connor, A Mayoh, C Venkat, P Quek, H Brand, J Kusuma, FK Pettitt, JA Mosmann, E Kearns, A Eden, G Alfred, S Allan, S Zhai, L Kamili, A Gifford, AJ Carter, DR Henderson, MJ Fletcher, JI Marshall, G Johnstone, RW Cesare, AJ Ziegler, DS Gudkov, AV Gurova, KV Norris, MD Haber, M

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Publisher:: American Association for Cancer Research (AACR)
Publication Type:: Journal Article
Citation:: Clin Cancer Res, 2021, 27, (15), pp. 4338-4352
Issue Date:: 2021-08-01

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Field	Value	Language
dc.contributor.author	Xiao, L
dc.contributor.author	Somers, K
dc.contributor.author	Murray, J
dc.contributor.author	Pandher, R
dc.contributor.author	Karsa, M
dc.contributor.author	Ronca, E
dc.contributor.author	Bongers, A
dc.contributor.author	Terry, R
dc.contributor.author	Ehteda, A
dc.contributor.author	Gamble, LD
dc.contributor.author	Issaeva, N
dc.contributor.author	Leonova, KI
dc.contributor.author	O'Connor, A
dc.contributor.author	Mayoh, C
dc.contributor.author	Venkat, P
dc.contributor.author	Quek, H
dc.contributor.author	Brand, J
dc.contributor.author	Kusuma, FK
dc.contributor.author	Pettitt, JA
dc.contributor.author	Mosmann, E
dc.contributor.author	Kearns, A
dc.contributor.author	Eden, G
dc.contributor.author	Alfred, S
dc.contributor.author	Allan, S
dc.contributor.author	Zhai, L
dc.contributor.author	Kamili, A
dc.contributor.author	Gifford, AJ
dc.contributor.author	Carter, DR
dc.contributor.author	Henderson, MJ
dc.contributor.author	Fletcher, JI
dc.contributor.author	Marshall, G
dc.contributor.author	Johnstone, RW
dc.contributor.author	Cesare, AJ
dc.contributor.author	Ziegler, DS
dc.contributor.author	Gudkov, AV
dc.contributor.author	Gurova, KV
dc.contributor.author	Norris, MD
dc.contributor.author	Haber, M
dc.date.accessioned	2022-04-18T19:09:30Z
dc.date.available	2021-04-16
dc.date.available	2022-04-18T19:09:30Z
dc.date.issued	2021-08-01
dc.identifier.citation	Clin Cancer Res, 2021, 27, (15), pp. 4338-4352
dc.identifier.issn	1078-0432
dc.identifier.issn	1557-3265
dc.identifier.uri	http://hdl.handle.net/10453/156334
dc.description.abstract	PURPOSE: We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma. EXPERIMENTAL DESIGN: The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction. RESULTS: The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination. CONCLUSIONS: The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	American Association for Cancer Research (AACR)
dc.relation.ispartof	Clin Cancer Res
dc.relation.isbasedon	10.1158/1078-0432.CCR-20-2357
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Carbazoles
dc.subject.mesh	Chromatin
dc.subject.mesh	Drug Combinations
dc.subject.mesh	Drug Evaluation, Preclinical
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Panobinostat
dc.subject.mesh	Tumor Cells, Cultured
dc.subject.mesh	Tumor Cells, Cultured
dc.subject.mesh	Chromatin
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Carbazoles
dc.subject.mesh	Drug Combinations
dc.subject.mesh	Drug Evaluation, Preclinical
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	Panobinostat
dc.title	Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma.
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/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	closed_access	*
dc.date.updated	2022-04-18T19:09:29Z
pubs.issue	15
pubs.publication-status	Published
pubs.volume	27
utslib.citation.issue	15

Abstract:

PURPOSE: We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma. EXPERIMENTAL DESIGN: The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction. RESULTS: The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination. CONCLUSIONS: The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.

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http://hdl.handle.net/10453/156334