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Low-dose histone deacetylase inhibitor treatment leads to tumor growth arrest and multi-lineage differentiation of malignant rhabdoid tumors

Muscat, Andrea, Popovski, Dean, Jayasekara, W. Samantha N., Rossello, Fernando J., Ferguson, Melissa, Marini, Kieren D., Alamgeer, Muhammad, Algar, Elizabeth M., Downie, Peter, Watkins, D. Neil, Cain, Jason E. and Ashley, David 2016, Low-dose histone deacetylase inhibitor treatment leads to tumor growth arrest and multi-lineage differentiation of malignant rhabdoid tumors, Clinical cancer research, vol. 22, no. 14, pp. 3560-3570, doi: 10.1158/1078-0432.CCR-15-2260.

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Title Low-dose histone deacetylase inhibitor treatment leads to tumor growth arrest and multi-lineage differentiation of malignant rhabdoid tumors
Author(s) Muscat, AndreaORCID iD for Muscat, Andrea orcid.org/0000-0003-1666-7961
Popovski, Dean
Jayasekara, W. Samantha N.
Rossello, Fernando J.
Ferguson, Melissa
Marini, Kieren D.
Alamgeer, Muhammad
Algar, Elizabeth M.
Downie, Peter
Watkins, D. Neil
Cain, Jason E.
Ashley, David
Journal name Clinical cancer research
Volume number 22
Issue number 14
Start page 3560
End page 3570
Total pages 11
Publisher American Association for Cancer Research
Place of publication Philadelphia, Penn.
Publication date 2016-07
ISSN 1557-3265
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Oncology
ATYPICAL TERATOID/RHABDOID TUMOR
STEM-CELL MARKERS
IN-VIVO
HDAC INHIBITORS
ERYTHROLEUKEMIC CELLS
ANTITUMOR-ACTIVITY
NERVOUS-SYSTEM
SOLID TUMORS
CANCER
EXPRESSION
Summary PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
Language eng
DOI 10.1158/1078-0432.CCR-15-2260
Field of Research 111299 Oncology and Carcinogenesis not elsewhere classified
1112 Oncology And Carcinogenesis
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, American Association for Cancer Research
Persistent URL http://hdl.handle.net/10536/DRO/DU:30085925

Document type: Journal Article
Collection: School of Medicine
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Created: Tue, 06 Sep 2016, 12:13:34 EST

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