Preclinical testing of the glycogen synthase kinase-3β inhibitor tideglusib for rhabdomyosarcoma
| Autor: | Jack F. Shern, Noah E. Berlow, David M. Langenau, Teagan P. Settelmeyer, Matthew N. Svalina, Megan M. Cleary, Ganapati Srinivasa, Narendra Bharathy, James B. Hayden, James G. Keck, Sunny Xiang, Atiya Mansoor, Charles Keller, Susan D. Airhart, Melvin Lathara |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty Pathology patient-derived xenograft genetic structures Oncogenomics myodifferentiation 03 medical and health sciences GSK-3 Internal medicine Medicine General hospital Rhabdomyosarcoma business.industry Molecular pathology GSK3β Cancer medicine.disease 3. Good health 030104 developmental biology Preclinical testing Alveolar rhabdomyosarcoma rhabdomyosarcoma preclinical testing business Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Narendra Bharathy 1 , Matthew N. Svalina 1 , Teagan P. Settelmeyer 1 , Megan M. Cleary 1 , Noah E. Berlow 1 , Susan D. Airhart 2 , Sunny Xiang 2 , James Keck 2 , James B. Hayden 3 , Jack F. Shern 4, 5 , Atiya Mansoor 6 , Melvin Lathara 7 , Ganapati Srinivasa 7 , David M. Langenau 8, 9 and Charles Keller 1 1 Children’s Cancer Therapy Development Institute, Beaverton, OR 97005, USA 2 The Jackson Laboratory, Sacramento, CA 95838, USA 3 Department of Orthopedics and Rehabilitation, Oregon Health & Science University, Portland, OR 97239, USA 4 Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA 5 Pediatric Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA 6 Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA 7 Omics Data Automation, Beaverton, OR 97005, USA 8 Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA 9 Harvard 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|