Due to a lack of effective screening or prevention protocol for
epithelial ovarian cancer (EOC), there is a critical unmet need to develop therapeutic interventions for EOC treatment. EOC
metastasis is unique. Initial dissemination is not primarily hematogenous, yet is facilitated through shedding of primary
tumor cells into the peritoneal fluid and accumulating
ascites. Increasingly, isolated patient spheroids point to a clinical role for spheroids in EOC
metastasis. EOC spheroids are highly invasive structures that disseminate upon peritoneal mesothelium, and visceral tissues including liver and omentum. Selection for this subset of chemoresistant EOC cells could influence
disease progression and/or recurrence. Thus, targeting spheroid integrity/structure may improve the chemotherapeutic responsiveness of EOC. We discovered a critical role for mammalian Diaphanous (mDia)-related formin-2 in maintaining EOC spheroid structure. Both mDia2 and the related mDia1 regulate
F-actin networks critical to maintain cell-cell contacts and the integrity of multi-cellular epithelial sheets. We investigated if mDia2 functional inhibition via a small molecule inhibitor SMIFH2 combined with chemotherapeutics, such as
taxol and
cisplatin, inhibits the viability of EOC monolayers and clinically relevant spheroids. SMIFH2-mediated mDia
formin inhibition significantly reduced both ES2 and Skov3 EOC monolayer viability while spheroid viability was minimally impacted only at the highest concentrations. Combining either
cisplatin or
taxol with SMIFH2 did not significantly enhance the effects of either drug alone in ES2 monolayers, while Skov3 monolayers treated with
taxol or
cisplatin and SMIFH2 showed significant additive inhibition of viability. ES2 spheroids were highly responsive with clear additive anti-viability effects with dual
taxol or
cisplatin when combined with SMIFH2 treatments. While combined
taxol with SMIFH2 in spheroids showed an additive effect relative to single treatments, Skov3 spheroids showed no additive effects from combined
cisplatin and SMIFH2 treatments. Our data indicate that mDia
formin inhibition combined with
taxol to drive enhanced and/or additive anti-viability effects targeting 3D EOC structures, including ES2 and Skov3 spheroids. Combined mDia
formin inhibition with
cisplatin may be most effective in EOC spheroids where
cisplatin sensitivity is retained at moderate levels, such as ES2 cells.