Long term, continuous exposure to panobinostat induces terminal differentiation and long term survival in the TH-MYCN neuroblastoma mouse model.

Abstract

Neuroblastoma is the most common extra-cranial malignancy in childhood and accounts for ∼15% of childhood cancer deaths. Amplification of MYCN in neuroblastoma is associated with aggressive disease and predicts for poor prognosis. Novel therapeutic approaches are therefore essential to improving patient outcomes in this setting. The histone deacetylases are known to interact with N-Myc and regulate numerous cellular processes via epigenetic modulation, including differentiation. In this study, we used the TH-MYCN mouse model of neuroblastoma to investigate the antitumor activity of the pan-HDAC inhibitor, panobinostat. In particular we sought to explore the impact of long term, continuous panobinostat exposure on the epigenetically driven differentiation process. Continuous treatment of tumor bearing TH-MYCN transgenic mice with panobinostat for nine weeks led to a significant improvement in survival as compared with mice treated with panobinostat for a three-week period. Panobinostat induced rapid tumor regression with no regrowth observed following a nine-week treatment period. Initial tumor response was associated with apoptosis mediated via upregulation of BMF and BIM. The process of terminal differentiation of neuroblastoma into benign ganglioneuroma, with a characteristic increase in S100 expression and reduction of N-Myc expression, occurred following prolonged exposure to the drug. RNA-sequencing analysis of tumors from treated animals confirmed significant upregulation of gene pathways associated with apoptosis and differentiation. Together our data demonstrate the potential of panobinostat as a novel therapeutic strategy for high-risk neuroblastoma patients.

• Authors: Kelly Waldeck, Carleen Cullinane, Kerry Ardley, Jake Shortt, Ben Martin, Richard W Tothill, Jason Li, Ricky W Johnstone, Grant A McArthur, Rodney J Hicks, Paul J Wood
• Journal: International journal of cancer (Int J Cancer) Vol. 139 Issue 1 Pg. 194-204 (Jul 01 2016) ISSN: 1097-0215 [Electronic] United States
• PMID: 26914605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 UICC.

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Indoles
• Proto-Oncogene Proteins c-myc
• S100 Proteins
• Panobinostat

Topics

• Animals
• Apoptosis (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (administration & dosage)
• Humans
• Hydroxamic Acids (administration & dosage)
• Indoles (administration & dosage)
• Male
• Mice
• Mice, Transgenic
• Neuroblastoma (drug therapy, genetics, pathology)
• Panobinostat
• Proto-Oncogene Proteins c-myc (biosynthesis)
• S100 Proteins (biosynthesis)
• Survival Analysis