1543P - Old friends are better to trust: Repositioning clofazimine and suramin against triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is the breast cancer subtype currently without targeted therapy. In our previous studies we identified that the human-use approved drugs clofazimine and suramin have shown a profound inhibitory activity towards Wnt pathway, which TNBC somatic cells use heavily. The accumulated over decades of application of these drugs will facilitate enrollment in clinical trials and repositioning as targeted treatments. We have characterized Wnt signaling status in various TNBC somatic and stem cell lines in presence of clofazimine and suramin through WB and immunofluorescence. We have also monitored their effects on cell survival, migration and colony formation in conventional assays, as well as on apoptosis and cell cycle. We have also used two mouse xenograft models to study the effects of the drugs on tumor growth in vivo followed by IHC and WB analysis of relevant markers of Wnt signaling pathway activation. Both drugs were found active in suppressing growth of a panel of TNBC cell lines as well as of CSC cell line in vitro, which correlates with their ability to suppress Wnt signal transduction. As expected, these drugs suppress proliferation as well as migration of the cancer cells – two processes that are governed by Wnt signaling. We have also investigated if these compounds could be used as the co-treatments by calculating their combination index. A similar trend was obtained in vivo, where suramin and clofazimine were able to suppress growth of the tumor xenografts without inducing significant overt side effects. Our data however presumes that suramin unlike clofazimine must be used at the doses significantly higher than those used for its intended purpose. This work is an attempt to translate our previous investigations on the molecular mechanisms of the clofazimine and suramin action in Wnt pathway and bring these advances to the level of clinics. Our results show that their anti-Wnt activity results in the ability to suppress TNBC growth in vivo with few or no side effects visible in xenografted animals. Challenges remain however to establish optimized regimen for their new application in order to maximize their efficacy and to perform trials with their usage as a co-therapy.