Oncotarget

Research Papers:

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

Narendra Bharathy _, Matthew N. Svalina, Teagan P. Settelmeyer, Megan M. Cleary, Noah E. Berlow, Susan D. Airhart, Sunny Xiang, James Keck, James B. Hayden, Jack F. Shern, Atiya Mansoor, Melvin Lathara, Ganapati Srinivasa, David M. Langenau and Charles Keller

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Oncotarget. 2017; 8:62976-62983. https://doi.org/10.18632/oncotarget.18520

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Abstract

Narendra Bharathy1, Matthew N. Svalina1, Teagan P. Settelmeyer1, Megan M. Cleary1, Noah E. Berlow1, Susan D. Airhart2, Sunny Xiang2, James Keck2, James B. Hayden3, Jack F. Shern4,5, Atiya Mansoor6, Melvin Lathara7, Ganapati Srinivasa7, David M. Langenau8,9 and Charles Keller1

1Children’s Cancer Therapy Development Institute, Beaverton, OR 97005, USA

2The Jackson Laboratory, Sacramento, CA 95838, USA

3Department of Orthopedics and Rehabilitation, Oregon Health & Science University, Portland, OR 97239, USA

4Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA

5Pediatric Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA

6Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA

7Omics Data Automation, Beaverton, OR 97005, USA

8Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA

9Harvard Stem Cell Institute, Cambridge, MA 02129, USA

Correspondence to:

Narendra Bharathy, email: [email protected]

Charles Keller, email: [email protected]

Keywords: rhabdomyosarcoma, preclinical testing, patient-derived xenograft, GSK3β, myodifferentiation

Received: December 07, 2016    Accepted: June 01, 2017    Published: June 16, 2017

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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