Preclinical testing of the glycogen synthase kinase-3β inhibitor tideglusib for rhabdomyosarcoma.
Preclinical testing of the glycogen synthase kinase-3β inhibitor tideglusib for rhabdomyosarcoma.
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DOI：
10.18632/oncotarget.18520
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发表时间：
2017-09-08
期刊：
影响因子：
--
通讯作者：
Keller C
中科院分区：
文献类型：
--
作者：
Bharathy N;Svalina MN;Settelmeyer TP;Cleary MM;Berlow NE;Airhart SD;Xiang S;Keck J;Hayden JB;Shern JF;Mansoor A;Lathara M;Srinivasa G;Langenau DM;Keller C
横纹肌肉瘤是儿童最常见的软组织肉瘤。横纹肌肉瘤通常起源于肌原性前体，表现为分化较差的骨骼肌表型，与再生肌最为相似。GSK 3 β是一种广泛表达的丝氨酸-苏氨酸激酶，能够抑制心肌和骨骼肌中的终末肌源性分化程序。最近的无偏化学筛选工作优先考虑将GSK 3 β抑制剂作为RMS中肌分化的诱导剂，这表明在斑马鱼转基因胚胎RMS（eRMS）模型中作为单一药物在体内抑制生长和促进自我更新中的功效。在这项研究中，我们测试了不可逆的GSK 3 β抑制剂tideglusib在患者来源的腺泡状横纹肌肉瘤（aRMS）和eRMS异种移植模型中的体内疗效。Tideglusib具有有效的靶向药效学疗效，但作为单药对肿瘤进展或肌分化无影响。这些结果表明，作为单药治疗，GSK 3 β抑制剂可能不是aRMS或eRMS的可行治疗方法。
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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影响因子：
5
作者：
Dionyssiou, M. G.;Nowacki, N. B.;McDermott, J. C.
通讯作者：
McDermott, J. C.
影响因子：
3.2
作者：
Blandford, MC;Barr, FG;Keller, C
通讯作者：
Keller, C
影响因子：
50.3
作者：
Rubin, Brian P.;Nishijo, Koichi;Keller, Charles
通讯作者：
Keller, Charles
影响因子：
10.5
作者：
Yost, C;Torres, M;Moon, RT
通讯作者：
Moon, RT
影响因子：
56.9
作者：
TAPSCOTT, SJ;THAYER, MJ;WEINTRAUB, H
通讯作者：
WEINTRAUB, H