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Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma.
Xiao, Lin; Somers, Klaartje; Murray, Jayne; Pandher, Ruby; Karsa, Mawar; Ronca, Emma; Bongers, Angelika; Terry, Rachael; Ehteda, Anahid; Gamble, Laura D; Issaeva, Natalia; Leonova, Katerina I; O'Connor, Aisling; Mayoh, Chelsea; Venkat, Pooja; Quek, Hazel; Brand, Jennifer; Kusuma, Frances K; Pettitt, Jessica A; Mosmann, Erin; Kearns, Adam; Eden, Georgina; Alfred, Stephanie; Allan, Sophie; Zhai, Lei; Kamili, Alvin; Gifford, Andrew J; Carter, Daniel R; Henderson, Michelle J; Fletcher, Jamie I; Marshall, Glenn; Johnstone, Ricky W; Cesare, Anthony J; Ziegler, David S; Gudkov, Andrei V; Gurova, Katerina V; Norris, Murray D; Haber, Michelle.
Afiliação
  • Xiao L; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Somers K; School of Women's and Children's Health, University of New South Wales Sydney, Randwick, New South Wales, Australia.
  • Murray J; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Pandher R; School of Women's and Children's Health, University of New South Wales Sydney, Randwick, New South Wales, Australia.
  • Karsa M; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Ronca E; School of Women's and Children's Health, University of New South Wales Sydney, Randwick, New South Wales, Australia.
  • Bongers A; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Terry R; School of Women's and Children's Health, University of New South Wales Sydney, Randwick, New South Wales, Australia.
  • Ehteda A; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Gamble LD; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Issaeva N; School of Women's and Children's Health, University of New South Wales Sydney, Randwick, New South Wales, Australia.
  • Leonova KI; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • O'Connor A; School of Women's and Children's Health, University of New South Wales Sydney, Randwick, New South Wales, Australia.
  • Mayoh C; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Venkat P; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Quek H; School of Women's and Children's Health, University of New South Wales Sydney, Randwick, New South Wales, Australia.
  • Brand J; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Kusuma FK; Department of Otolaryngology/Head and Neck Surgery, Department of Pathology and Lab Medicine, Lineberger Comprehensive Cancer Center, UNC-Chapel Hill, Chapel Hill, North Carolina.
  • Pettitt JA; Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York.
  • Mosmann E; Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.
  • Kearns A; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Eden G; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Alfred S; Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  • Allan S; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Zhai L; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Kamili A; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Gifford AJ; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Carter DR; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Henderson MJ; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Fletcher JI; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Marshall G; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Johnstone RW; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Cesare AJ; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Ziegler DS; School of Women's and Children's Health, University of New South Wales Sydney, Randwick, New South Wales, Australia.
  • Gudkov AV; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Gurova KV; School of Women's and Children's Health, University of New South Wales Sydney, Randwick, New South Wales, Australia.
  • Norris MD; Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
  • Haber M; School of Women's and Children's Health, University of New South Wales Sydney, Randwick, New South Wales, Australia.
Clin Cancer Res ; 27(15): 4338-4352, 2021 08 01.
Article em En | MEDLINE | ID: mdl-33994371
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carbazóis / Cromatina / Inibidores de Histona Desacetilases / Panobinostat / Neuroblastoma Limite: Animals Idioma: En Revista: Clin Cancer Res Assunto da revista: NEOPLASIAS Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Austrália
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carbazóis / Cromatina / Inibidores de Histona Desacetilases / Panobinostat / Neuroblastoma Limite: Animals Idioma: En Revista: Clin Cancer Res Assunto da revista: NEOPLASIAS Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Austrália