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Title: Study of gene expression changes in TH-MYCN murine neuroblastomas in response to 24hr of panobinostat treatment      
dateReleased:
07-15-2015
description:
Neuroblastoma is the most common extra-cranial malignancy in childhood and accounts for approximately 15% of childhood cancer deaths. Amplification of N-Myc 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, including differentiation in neuroblastoma. We therefore investigated the antitumor activity of the histone deacetylase inhibitor, panobinostat in the setting of N-Myc amplified neuroblastoma using the TH-MYCN murine model. Continuous treatment of tumor bearing TH-MYCN transgenic mice with panobinostat for 9 weeks led to a significant improvement in survival as compared to mice treated with vehicle, or continuous treatment with panobinostat for a three week period. Panobinostat induced rapid tumor regression with no regrowth observed during the treatment period. Tumor response was associated with an initial apoptosis phenotype mediated via up-regulation of BMF and BIM. When treated was stopped at three weeks 100% of mice relapsed with aggressive neuroblastoma. Differentiation of neuroblastoma into benign ganglioneuroma, with a characteristic increase in S100 expression and reduction of N-Myc expression, was observed in mice treated for nine weeks, resulting in a sustained remission on 90% of mice treated. RNA-sequencing analysis of tumors from treated animals confirmed significant up-regulation of gene pathways associated with apoptosis and differentiation as early as 24 hours after treatment. Together our data demonstrate the potential of panobinostat as a therapeutic strategy for high-risk neuroblastoma patients. Eight homozygous TH-MYCN mice bearing neuroblastomas were treated with either 5mg/kg panobinostat (4 animals) or vehicle (4 animals) for 24hr (two doses) and tumours harvested 4hr post the second dose.
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-GEOD-69869
refinement:
raw
alternateIdentifiers:
69869
keywords:
functional genomics
dateModified:
12-21-2015
availability:
available
types:
gene expression
name:
Mus musculus
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-69869/E-GEOD-69869.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-69869/E-GEOD-69869.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69869
storedIn:
Gene Expression Omnibus
qualifier:
not compressed
format:
HTML
accessType:
landing page
primary:
true
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress
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