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Page 290 Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010

relevant signaling pathways and processes participating in platinum resistance include Wnt, PI3K/Akt,
Notch, NF-κB and EMT. As specified above, epigenetic therapies appear to be promising therapy strategies.
Combined administration of DNMT and HDAC inhibitors may re-express silenced tumor suppressor genes.
Moreover, changes in the methylation profiles of ovarian cancer have led to the testing of new combination
treatment regimes. Therapeutics to inhibit DNMT, including azacitidine and decitabine, were successfully
developed and approved for treatment. In 2010, Fang et al. were the first to assess decitabine at repeated
[79]
low doses to reduce DNA methylation and re-instate cisplatin sensitivity in a Phase 1 clinical trial of HGSOC
patients. Other therapeutic agents that target methylation include SGI-110 as a nucleoside analogue and
valproic acid, and seem to be beneficial in the treatment of diverse cancer types.

Further epigenetic targets could be miRNAs that are also involved in tumor suppressor silencing.
Accordingly, miRNAs are attractive candidates for developing a new class of drugs that specifically target
miRNA pathways. For example, promising targets to date are miR-622 that targets the Ku pathway and
[146]
miR-484 that targets both VEGFB and VEGFR2 pathways as well as tumor vasculature . As reviewed
[187]
above, many other miRNAs have also been associated with resistance to cis- and carboplatin in ovarian
cancer. Therefore, determining which miRNAs are the best for miRNA targeted therapy development will be a
challenge. In this regard, several mechanisms to target miRNAs are currently in development for cancer treatment.
Down-regulation of target oncogenes by re-expression of tumor suppressor miRNAs, or re-expression of tumor
suppressor genes by silencing of oncogenic miRNAs is anticipated to sensitize tumor to platinum treatment.
Restoring and blocking miRNA function may be performed by replacement of tumor suppressor miRNAs
with either synthetic or viral vectors encoded for miRNA mimics, or by antisense-mediated inhibition of
oncogenic miRNAs, respectively. The above studies provide promising results to re-sensitize both ovarian
cancer cell lines and animal models to platinum therapy, so laying the basis for effective epigenetic drugs in
combination with platinum-based agents. In future, cis- or carboplatin therapies combined with epigenetic
drugs may shed light on the potential of personalized treatment modalities to overcome resistance in women
with recurrent ovarian cancer.

DECLARATIONS
Authors’ contributions
Both authors contribute equally to the manuscript.

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Conflicts of interest
Both authors declare that there are no conflicts of interest.

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Copyright
© The Author(s) 2019.