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Page 2 of 5 Judson. J Cancer Metastasis Treat 2021;7:28 https://dx.doi.org/10.20517/2394-4722.2021.110

translocation.

The latest edition of the WHO Classification of Tumors of Soft Tissue and Bone, published in 2020, lists
many more sarcomas that are now classified by their molecular characteristics, such as those driven by a
CIC-DUX4 fusion gene, previously a subset of Ewing sarcoma-like small round cell tumours lacking an
EWSR1 fusion. While it is now known that this is a distinct entity, characterised by an aggressive clinical
[6]
course and poor response to chemotherapy , this knowledge has not resulted in a targeted therapy. The
synovial sarcoma story warns us to be patient.

There are some recent successes, for example the use of ALK inhibitors such as crizotinib in the treatment
of inflammatory myofibroblastic tumour , and the approval by the FDA of the EZH2 inhibitor tazemetostat
[7]
for the treatment of epithelioid sarcoma following the report of responses and improved survival in a basket
[8]
trial . In this current issue devoted to the topic of sarcomas we have a number of articles also relating to the
identification of known or potential new targets for therapy, but also papers on surgical technique and
survivorship.

The paper by Karolak and colleagues focuses on the role of EZH2, a histone methyltransferase which is a
[9]
component of the chromatin-modifying complex PRC2 (Polycomb Repressive Complex 2). EZH2 is
responsible for adding methyl groups to Lysine 27 on histone H3. The resultant H3K27Me3 mark is an
important repressive signal, resulting in condensation of chromatin and inhibiting transcription of the
associated gene(s). A number of sarcomas, such as MPNST, synovial sarcoma, leiomyosarcoma, epithelioid
sarcoma and rhabdomyosarcoma are associated with overexpression of EZH2.

Overexpression is associated with a worse prognosis and a higher rate of distant metastasis. The effects of
EZH2 activity include inhibition of terminal differentiation and senescence and maintenance of
proliferation. Some sarcomas are characterised by loss of a component of the SW1/SNF chromatin-
remodelling complex, SMARCB1, also known as INI1. SW1/SNF has opposing activity to PRC2 and
mutations in SMARCB1 may result in loss of function of this subunit, hence of the SW1/SNF complex
resulting in effective upregulation of PRC2, hence EZH2. The EZH2 inhibitor tazemetostat has
demonstrated significant activity against epithelioid sarcoma, a diseases for which loss of INI1 has long been
[8]
known to be a diagnostic marker, with a 15% response rate and median overall survival of 19 months . In
the same study patients with synovial sarcoma, also with INI1 loss, were included but best response was
stable disease (SD), with 15% of patients having durable SD for > 16 weeks. Loss of INI1 is clearly
insufficient to predict substantial anti-tumour activity with EZH2 inhibition. Laboratory studies appear to
indicate that downregulation of EZH2 inhibits tumour growth in tumours with EZH2 overexpression, but
this may not consistently translate into activity with EZH2 inhibitors in the clinic.

[10]
The paper by Abe et al. reviews the role of glycogen synthase kinase 3β (GSK3β) in sarcomas. GSK3β is
an enzyme that phosphorylates glycogen synthase, and other important proteins, on serine and threonine
residues. There is growing evidence that GSK3β can play a role in tumorigenesis and extensive
investigations have confirmed it as a potential therapeutic target in a number of different malignancies .
[11]
One of the key mechanisms appears to be positive transcriptional control of NF-κB and subsequent cancer
cell survival and resistance to chemotherapy. In their review of the data linking GSK3β expression and
activation to sarcomas Abe et al. first discuss the knowledge to date on molecularly targeted therapy of
[10]
sarcomas and makes a persuasive case that GSK3β plays an important role in a number of sarcomas and
may be a useful target for novel therapy. In osteosarcoma, a disease sorely in need of new treatment, the
active form of GSK3β is overexpressed compared to normal osteoblasts and inhibition results in reduced