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Karolak et al. J Cancer Metastasis Treat 2021;7:15 https://dx.doi.org/10.20517/2394-4722.2021.05 Page 9 of 16

inhibition in ARMS led to apoptosis, whereas in ERMS resulted in induction of differentiation. The possible
interpretation of these may be that both subtypes originate from the same cellular lineage but undergo
[49]
distinct differentiation pathways and generate specific clinical phenotypes , which determines their
response to the therapy.

A more recent paper describes a new treatment approach involving dual “hybrid” EZH2/HDAC inhibitor in
RH4 cell line. This strategy led to cell cycle arrest, apoptotic events, affected cell viability, enhanced
differentiation and reduction of H3K27me3. The higher doses of the dual drug were more efficient and
[50]
worked in an intensified manner , which confirms the more complex or combined treatment in STS at
certain conditions works better than monotherapy. Accordingly, the concurrent administration of
TPA/GSK126 and Vincristine to chemoresistant and undifferentiated MYOD1+/NOG+ ERMS cells led to
enhanced effectiveness of the therapy and increased synergy. The administration of TPA/GSK126 at first
showed growing levels of MYOG protein, indicating cell differentiation. Following treatment with
vincristine, higher decreases in cell viability and reduction of surviving RMS cells were observed, suggesting
drugs synergy . Administration of DZNep to ERMS cells led to restoration of several micro-RNAs, such as
[51]
miR-29b, miR-214 and miR-101. The same results were obtained through forced expression of a mature
miR-101 precursor, leading to restoration of miR-101 levels, followed by down-regulation of both mRNA
and protein levels of EZH2 and therefore, reduction of the tumorigenic potential of ERMS cells in vitro.
These discoveries confirm the miR-101 is directly targeted by EZH2 and lower levels of this microRNA may
[2]
contribute to EZH2 overexpression and hence, promote cancer progression in ERMS . In contrast to these
findings, the Paediatric Preclinical Testing Program (PPTP) study demonstrated that administration of the
highly potent and EZH2-selective inhibitor tazemetostat as a single agent in ARMS mouse xenografts did
not show promising antitumour activity .
[52]

Malignant rhabdoid tumours
The effectiveness of tazemetostat has also been tested against rhabdoid tumours in vivo by the PPTP.
Tazemetostat was administered to immunodeficient mouse MRT xenografts, demonstrating significant
antitumor activity and differences observed in event free survival (EFS) in 5 out of 7 rhabdoid xenografts,
compared to non-rhabdoid models. Both, MRT and ATRT xenografts in which the EZH2 inhibition was the
[52]
most effective, were identified as SMARCB1-deficient . In another study, administration of EPZ-6438 in
MRT cells led to a dose-dependent decrease in H3K27me3, with other histone epigenetic marks being
unaffected. Furthermore, proliferation of cancerous cells was significantly reduced compared to control
SMARCB1 wild-type cells. EPZ-6438 treatment in immunocompromised mouse xenografts bearing G401
cells showed completed elimination of the tumour without recurrence after termination of dosing. Smaller
[6]
doses of the drug resulted in stable tumour growth at first, followed by delay in growth . Another approach
evaluating DZNep in combination with conventional cytostatic drugs (doxorubicin/etoposide) or epigenetic
agents (5-Aza-CdR/SAHA) to three, anatomically distinct MRT cell lines (kidney, brain, and liver)
displayed significantly synergy. Addition of DZNep led to remarkable intensification of anti-proliferative
[7]
outcome in vitro , except for treatment with doxorubicin, in which addition of DZNep did not show
[53]
significant differences . In another study, treatment of G401 cells with GSK126, GSK343 or UNC1999
showed reduction of H3K27me3 levels and only modest inhibition of cell proliferation. Furthermore, the
combination of a histone deacetylase inhibitor, Panobinostat, with GSK126 resulted in a significant
reduction in EZH2 expression, and anti-proliferative and pro-differentiation effects in vitro and in vivo,
compared to use of a single agent , as demonstrated in other tumour types [54-57] .
[40]

Atypical teratoid rhabdoid tumours
In ATRTs, use of DZNep resulted in anti-proliferative and pro-apoptotic effects, increased sensitivity of
cancerous cells to radiation and decreased ability to self-renewal and to form tumour spheres . Another
[39]