Glycogen synthase kinase 3β biology in bone and soft tissue sarcomas

Abstract

Bone and soft tissue sarcomas are malignant neoplasms probably originating from musculoskeletal and mesenchymal progenitor cells. More than 80 different histopathological subtypes are encountered in orthopedics. The standard of care for sarcoma patients involves a multidisciplinary combination of surgery, anthracycline-based multiagent chemotherapy and radiation. Unfortunately, these are associated with adverse events and occasionally disappointing outcomes. Various genomic-, biologically-, and immunologically-based therapies are still under evaluation in early-phase clinical trials. However, there are strong barriers to the development and clinical translation of new therapeutic modalities. This is due to the rarity of these diseases, the broad spectrum of tumor subtypes with genetic and biological heterogeneity, and the wide variability in clinical manifestation, response to treatment and prognosis. A potential approach toward overcoming this barrier is to identify therapeutic targets that cover multiple sarcoma types. Glycogen synthase kinase 3β (GSK3β) has emerged as a common therapeutic target in more than 25 different cancer types. Here we review the evidence for tumor-promoting roles of GSK3β in the major types of bone and soft tissue sarcomas including osteosarcoma, rhabdomyosarcoma, synovial sarcoma, and fibrosarcoma. In this review, we describe the therapeutic effects of inhibiting GSK3β in these sarcoma types, while also protecting healthy cells and tissues from detrimental effects associated with conventional therapies, such as doxorubicin-induced cardiotoxicity. Consequently, we highlight GSK3β as a potential therapeutic target spanning multiple sarcoma types.

Keywords

Osteosarcoma / rhabdomyosarcoma / synovial sarcoma / fibrosarcoma / glycogen synthase kinase 3β

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