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Page 10 of 16 Karolak et al. J Cancer Metastasis Treat 2021;7:15 https://dx.doi.org/10.20517/2394-4722.2021.05

study showed that cell viability was significantly impaired in vitro, but administration of DZNep in vivo did
[58]
not change the survival time relative to control or systemic-treated/combination-treated xenografts . By
contrast, in the PPTP study, administration of tazemetostat to immunodeficient mouse ATRT xenografts
[52]
led to significant differences in EFS, compared to control . This suggests that EZH2-specific inhibition as a
single agent is unlikely to be a credible therapeutic option for these patients. Another combination therapy
to be tested in ATRT was GSK126 with JQ1 (a bromodomain inhibitor). This resulted in enhanced
inhibition of cell proliferation and invasion in vitro, suppressed tumour growth and extended survival in
mouse xenografts, compared to the use of each drug alone .
[59]
Epithelioid sarcoma
A study involving patient-derived INI1-negative ES tumour samples xenotransplanted to immunodeficient
mice and administration of EPZ011989 resulted in tumour growth stabilization at first, followed by tumour
volume inhibition of up to 89% and decreased H3K27me3 [60,61] . A clinical trial of patients with
SMARCB1(INI1)-negative ES treated with tazemetostat showed similar results to SS patients. Of 62 treated
participants, with a median of 1 prior therapy, 15% exhibited partial responses with objective response rate
and disease control rate of 15% and 26%, respectively. The duration of response to the treatment ranged
from 7.1 to 103.0 weeks and a median overall survival of 82.4 weeks was observed for all 62 patients .
[60]
Other STS Subtypes (MPNST, LMS, LS)
A study involving NF1-mutant (S462) and non-NF-1 mutated MPNST (MPNST724) cell lines treated with
DZNep demonstrated dose-dependent apoptosis of the cells in vitro relative to untreated normal human
Schwann cells. The viability of the cells, measured by the MTT assay, was significantly reduced from 100%
to 30% and 50% in S462 and MPNST724 cell lines, respectively. Cell cycle profiles were also altered,
indicating cell cycle arrest and inhibition of cell proliferation. Administration of DZNep in
immunodeficient mouse xenograft models led to significant reduction of tumour volume, especially at
higher doses. Subsequent immunohistochemical analyses revealed inhibition of cell proliferation and
[62]
induction of apoptosis in vivo .

In leiomyosarcoma cell lines, treatment with EPZ011989 resulted in a noticeable decrease in H3K27me3
levels compared to control. Furthermore, in BEZ235-resistant cells prior treatment with EPZ011989
significantly increased their sensitivity to BEZ235 (dactolisib, a dual PI3K/mTOR inhibitor) and a reduction
of cancer stem cells (CSCs). In xenografts, pre-treatment with EPZ001989 in combination with BEZ235 led
[63]
to a significant reduction in tumour growth compared to either drug alone .
Treatment of well-differentiated and dedifferentiated liposarcoma cell lines with GSK343 led to reduction of
cell proliferation, followed by a decrease in levels of H3K27me3 . Similarly, combination therapy using
[41]
GSK126 and 5-aza-dC, a chemical analog of cytidine, in a dedifferentiated cell line showed anti-proliferative
effects with a subsequent increased apoptosis and enhanced expression of adipocytes-specific differentiation
genes . These findings suggest combining epigenetic drugs may be more effective than single agents alone.
[64]
A number of clinical trials involving STS patients treated with small molecule inhibitors of EZH2 are
currently ongoing. These include treatment with tazemetostat of patients with SS, ES or SMARCB1-
deficient tumours (NCT02601937, NCT02875548 and NCT02601950). The combined approach of
tazemetostat and doxorubicin is also being tested in a clinical trial for patients with advanced ES
(NCT04204941).