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

Abstract

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> 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: naren@cc-tdi.org Charles Keller, email: charles@cc-tdi.org 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.