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

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.

GSK-3 Inhibitors: A Double-Edged Sword? – An Update on Tideglusib

“…Interestingly, in this study 50 nM of tideglusib for a period of 4 weeks was sufficient to induce Wnt activation further leading to increased mineralization and dentine formation [75]. A more recent study of tideglusib in rhabdomyosarcoma proved ineffective against tumor progression and myogenic differentiation though proving effective in pharmacodynamic efficacy [76]. Tideglusib has gained intense interest in the last two years and scientists have explored different application for small molecule inhibitor-tideglusib, ranging from a drug with high therapeutic potential to a promising radiotracer.…”

Establishment and Characterization of Histologically and Molecularly Stable Soft-tissue Sarcoma Xenograft Models for Biological Studies and Preclinical Drug Testing

“…Previously, other groups had established stable PDX models of myxoid liposarcoma (n ¼ 7), uterine leiomyosarcoma (n ¼ 10), MPNST (n ¼ 5), SFT (n ¼ 2), undifferentiated pleomorphic sarcoma (n ¼ 1), alveolar rhabdomyosarcoma (n ¼ 1), embryonal rhabdomyosarcoma (n ¼ 1), and CIC-DUX4 sarcoma (n ¼ 1; refs. [30][31][32][33][34][35][36]. However, this is the first report on the establishment of several other STS PDX subtypes using identical methodology and infrastructure, including some common subtypes such as myxofibrosarcoma and synovial sarcoma, but also some ultrarare entities such as epithelioid hemangioendothelioma, pulmonary artery intimal sarcoma, and mesenchymal chondrosarcoma.…”

Canonical WNT/β-Catenin Signaling Plays a Subordinate Role in Rhabdomyosarcomas

“…However, these results are in contrast to our recently published data suggesting that it is the main interaction partner of β-catenin, LEF1, which suppresses aggressiveness and induces myodifferentiation of RMS cells, whereas β-catenin activity plays a subordinate role in these processes (13). In addition, a recently published paper by Bharathy et al showed that activation of the canonical WNT signaling pathway in RMS in a patient derived xenograft model does not influence myodifferentiation or tumor progression (14). In the present work we try to unravel the impact of canonical WNT signaling and of β-catenin on aggressiveness and differentiation of RMS cells by (i) stimulation of RMS cell lines with WNT3A, (ii) β-catenin knockdown, (iii) using FH535, a small-molecule that inhibits β-catenin/TCF mediated transcription (15), and (iv) using XAV939 that antagonizes WNT signaling through AXIN stabilization and β-catenin degradation (16).…”