PUBLICATION

Preclinical testing of the glycogen synthase kinase-3β inhibitor tideglusib for rhabdomyosarcoma

Authors
Bharathy, N., Svalina, M.N., Settelmeyer, T.P., Cleary, M.M., Berlow, N.E., Airhart, S.D., Xiang, S., Keck, J., Hayden, J.B., Shern, J.F., Mansoor, A., Lathara, M., Srinivasa, G., Langenau, D.M., Keller, C.
ID
ZDB-PUB-171004-10
Date
2017
Source
Oncotarget   8: 62976-62983 (Journal)
Registered Authors
Langenau, David
Keywords
GSK3β, myodifferentiation, patient-derived xenograft, preclinical testing, rhabdomyosarcoma
MeSH Terms
none
PubMed
28968964 Full text @ Oncotarget
Abstract
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. RMS often arise from myogenic precursors and displays a poorly differentiated skeletal muscle phenotype most closely resembling regenerating muscle. GSK3β is a ubiquitously expressed serine-threonine kinase capable of repressing the terminal myogenic differentiation program in cardiac and skeletal muscle. Recent unbiased chemical screening efforts have prioritized GSK3β inhibitors as inducers of myodifferentiation in RMS, suggesting efficacy as single agents in suppressing growth and promoting self-renewal in zebrafish transgenic embryonal RMS (eRMS) models in vivo. In this study, we tested the irreversible GSK3β-inhibitor, tideglusib for in vivo efficacy in patient-derived xenograft models of both alveolar rhabdomyosarcoma (aRMS) and eRMS. Tideglusib had effective on-target pharmacodynamic efficacy, but as a single agent had no effect on tumor progression or myodifferentiation. These results suggest that as monotherapy, GSK3β inhibitors may not be a viable treatment for aRMS or eRMS.
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping