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

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.

• Authors: Lin Xiao, Klaartje Somers, Jayne Murray, Ruby Pandher, Mawar Karsa, Emma Ronca, Angelika Bongers, Rachael Terry, Anahid Ehteda, Laura D Gamble, Natalia Issaeva, Katerina I Leonova, Aisling O'Connor, Chelsea Mayoh, Pooja Venkat, Hazel Quek, Jennifer Brand, Frances K Kusuma, Jessica A Pettitt, Erin Mosmann, Adam Kearns, Georgina Eden, Stephanie Alfred, Sophie Allan, Lei Zhai, Alvin Kamili, Andrew J Gifford, Daniel R Carter, Michelle J Henderson, Jamie I Fletcher, Glenn Marshall, Ricky W Johnstone, Anthony J Cesare, David S Ziegler, Andrei V Gudkov, Katerina V Gurova, Murray D Norris, Michelle Haber
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 15 Pg. 4338-4352 (08 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33994371 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• CBLC137
• Carbazoles
• Chromatin
• Drug Combinations
• Histone Deacetylase Inhibitors
• Panobinostat

Topics

• Animals
• Carbazoles (administration & dosage, pharmacology)
• Chromatin (drug effects)
• Drug Combinations
• Drug Evaluation, Preclinical
• Histone Deacetylase Inhibitors (administration & dosage, pharmacology)
• Mice
• Neuroblastoma (drug therapy)
• Panobinostat (administration & dosage, pharmacology)
• Tumor Cells, Cultured