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Page 2 of 15 Abe et al. J Cancer Metastasis Treat 2020;6:51 I http://dx.doi.org/10.20517/2394-4722.2020.117

INTRODUCTION
Sarcomas are rare malignant neoplasms of putative mesenchymal resident (progenitor) cell origin that
[1,2]
comprise 20% of all bone sarcomas and 80% of all soft tissue sarcomas . They account for almost 1% of
[3]
newly diagnosed malignancies and deaths from the disease . Sarcomas can arise at almost any anatomical
site and occur most often in children, adolescents, and young adults. More than 80 histopathological
[4]
subtypes of sarcomas are defined by the updated WHO classification , with wide variability in their
clinical manifestation, response to treatment and prognosis. Accurate and differential diagnosis of the
respective sarcoma types is challenging because of their similarity and overlapping morphological features.
Several new approaches for cytogenetic, molecular, and immunohistochemical testing methods have
[5,6]
been combined with clinical and histopathological evaluation . The wide variety of tumor subtypes
with a difficult histopathologic diagnosis and the occurrence of tumors at many possible anatomical sites
complicate the overall biological and clinical understanding of bone and soft tissue sarcomas. Hence, the
[7,8]
current clinical practice guidelines for bone and soft tissue sarcomas do not adequately cover patient
management for all sarcoma types.

Surgery remains the mainstay of treatment for most sarcoma patients with localized tumor. This is often
combined with chemotherapy and/or radiation in neoadjuvant and adjuvant settings. Patients with
metastasis, at initial diagnosis or after curative surgery, undergo chemotherapy and radiation, either alone
[7,8]
or in combination . Currently, anthracycline-based chemotherapy is widely accepted as the first-line
therapy for most patients with advanced sarcoma. Doxorubicin remains a pivotal agent and is prescribed
in various combinations with other chemotherapeutics including ifosfamide, dacarbazine, gemcitabine,
and docetaxel. However, the empirical cytotoxic chemotherapies are associated with disappointing patient
outcomes and inevitable adverse effects, even when combined with new generation anticancer agents such
as eribulin and trabectedin [9,10] .

Recently, major efforts to decipher the genomic, epigenomic, and other biological properties of various
sarcoma types have identified several actionable molecular targets with potential therapeutic application.
Some of the molecular alterations found in sarcomas include activation of mutations in the c-kit and B-raf
genes, gene translocation involving growth factors such as platelet-derived growth factor (PDGF) receptor
(PDGFR) and colony stimulating factor 1 receptor, gene translocation involving transcription factors such
as vascular endothelial growth factor receptor (VEGFR), inactivation of tumor suppressor genes (TSC1/2
and PTEN) leading to activation of mechanistic target of rapamycin (mTOR), and overexpression of
PDGFR and VEGFR [11-15] . Several agents developed against these actionable targets have been tested in
clinical trials of advanced sarcoma patients and preliminary results shown improved survival. However,
most clinical trials for sarcoma remain in the early stages (phase I or phase II) [11,16,17] . The rarity of
sarcoma, the wide variety of histological subtypes and the lack of predictive biomarkers are major hurdles
in the clinical evaluation of available targeted agents. Consequently, ongoing clinical trials have yet to
show a significant survival benefit of the targeted agents over conventional chemotherapy. Identification
of therapeutic targets that span multiple sarcoma subtypes is therefore required to break the current
deadlock in developing innovative sarcoma therapies. This review focuses on glycogen synthase kinase 3b
(GSK3b) as an emerging and common therapeutic target in major sarcoma types including osteosarcoma,
rhabdomyosarcoma, synovial sarcoma, and fibrosarcoma that are frequently encountered in orthopedics.

OVERVIEW OF GSK3b BIOLOGY AND DISEASES
GSK3b was initially identified as an isoform of the GSK3 family of protein kinases. In addition to its
primary function of phosphorylating and thus inactivating glycogen synthase, GSK3b phosphorylates
serine and threonine residues in various functional and structural proteins, thereby serving multipurpose
roles in pivotal cellular pathways. GSK3b is constitutively active in cells upon tyrosine 216 phosphorylation
S9
Y216
(pGSK3b ). Negative regulation of its activity via serine 9 phosphorylation (pGSK3b ) occurs to control