title: 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.affiliation: Peter MacCallum Cancer Centre, Translational Research Laboratory, East Melbourne, VIC, Australia.
authors.forename: Kelly
authors.initials: K
authors.lastname: Waldeck
authors.affiliation: Peter MacCallum Cancer Centre, Translational Research Laboratory, East Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.affiliation: Peter MacCallum Cancer Centre, Translational Research Laboratory, East Melbourne, VIC, Australia.
authors.forename: Kerry
authors.initials: K
authors.lastname: Ardley
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.|Peter MacCallum Cancer Centre, Gene Regulation Laboratory, East Melbourne, VIC, Australia.|School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
authors.forename: Jake
authors.initials: J
authors.lastname: Shortt
authors.affiliation: Peter MacCallum Cancer Centre, Gene Regulation Laboratory, East Melbourne, VIC, Australia.
authors.forename: Ben
authors.initials: B
authors.lastname: Martin
authors.affiliation: Peter MacCallum Cancer Centre, Translational Research Laboratory, East Melbourne, VIC, Australia.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tothill
authors.affiliation: Peter MacCallum Cancer Centre, Bioinformatics Core Facility, East Melbourne, VIC, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.|Peter MacCallum Cancer Centre, Gene Regulation Laboratory, East Melbourne, VIC, Australia.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.affiliation: Peter MacCallum Cancer Centre, Translational Research Laboratory, East Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.|Department of Medicine, St.Vincent's Hospital, Fitzroy, VIC, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: Peter MacCallum Cancer Centre, Translational Research Laboratory, East Melbourne, VIC, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.affiliation: Peter MacCallum Cancer Centre, Translational Research Laboratory, East Melbourne, VIC, Australia.|Children's Cancer Centre, Monash Health, Clayton, VIC, Australia.|Department of Paediatrics, Monash University, Clayton, VIC, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077767:Panobinostat; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D009418:S100 Proteins / Q000096:biosynthesis; D016019:Survival Analysis
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D016271:Proto-Oncogene Proteins c-myc; D009418:S100 Proteins; D000077767:Panobinostat
keywords: HDAC inhibitors; TH-MYCN mouse model; differentiation; neuroblastoma; panobinostat