title: Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors.
abstract: Malignant rhabdoid tumor (MRT) and atypical teratoid rhabdoid tumors (ATRT) are rare aggressive undifferentiated tumors primarily affecting the kidney and CNS of infants and young children. MRT are almost exclusively characterized by homozygous deletion or inactivation of the chromatin remodeling gene SMARCB1 SMARCB1 protein loss leads to direct impairment of chromatin remodeling and we have previously reported a role for this protein in histone acetylation. This provided the rationale for investigating the therapeutic potential of histone deactylase inhibitors (HDACi) in MRT.
  
  
  
  Whereas previously HDACis have been used at doses and schedules that induce cytotoxicity, in the current studies we have tested the hypothesis, both in vitro and in vivo, that sustained treatment of human MRT with low-dose HDACi can lead to sustained cell growth arrest and differentiation.
  
  
  
  Sustained low-dose panobinostat (LBH589) treatment led to changes in cellular morphology associated with a marked increase in the induction of neural, renal, and osteoblast differentiation pathways. Genome-wide transcriptional profiling highlighted differential gene expression supporting multilineage differentiation. Using mouse xenograft models, sustained low-dose LBH589 treatment caused tumor growth arrest associated with tumor calcification detectable by X-ray imaging. Histological analysis of LBH589-treated tumors revealed significant regions of ossification, confirmed by Alizarin Red staining. Immunohistochemical analysis showed increased TUJ1 and PAX2 staining suggestive of neuronal and renal differentiation, respectively.
  
  
  
  Low-dose HDACi treatment can terminally differentiate MRT tumor cells and reduce their ability to self-renew. The use of low-dose HDACi as a novel therapeutic approach warrants further investigation. Clin Cancer Res; 22(14); 3560-70. ©2016 AACR.
authors.affiliation: Cancer Services, Barwon Health, Geelong, Victoria, Australia. School of Medicine, Deakin University, Geelong, Victoria, Australia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Muscat
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: Dean
authors.initials: D
authors.lastname: Popovski
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: W Samantha N
authors.initials: WS
authors.lastname: Jayasekara
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Rossello
authors.affiliation: Cancer Services, Barwon Health, Geelong, Victoria, Australia. School of Medicine, Deakin University, Geelong, Victoria, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Ferguson
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: Kieren D
authors.initials: KD
authors.lastname: Marini
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Medical Oncology, Monash Medical Centre, East Bentleigh, Victoria, Australia.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Alamgeer
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Algar
authors.affiliation: Children's Cancer Centre, Monash Children's Hospital, Monash Health, Victoria, Australia. Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Downie
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Watkins
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia. Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia. david.ashley@barwonhealth.org.au Jason.cain@hudson.org.au.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Cain
authors.affiliation: Cancer Services, Barwon Health, Geelong, Victoria, Australia. School of Medicine, Deakin University, Geelong, Victoria, Australia. david.ashley@barwonhealth.org.au Jason.cain@hudson.org.au.
authors.forename: David M
authors.initials: DM
authors.lastname: Ashley
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D000077767:Panobinostat; D018335:Rhabdoid Tumor / Q000188:drug therapy*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat