Transformed epithelial cells can activate embryonic programmes of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype also referred to as epithelial-to-mesenchymal transition (EMT). EMT is associated with poor prognosis in patients with osteotropic cancers. E-cadherin (CDH1) is an essential homotypic cell adhesion molecule that is often down regulated during this process. EMT-like processes are increasingly linked to therapy resistance and metastasis-initiating cells, thus providing the rationale for the development of novel small-molecule inhibitors that i) block the acquisition of an invasive phenotype in osteotropic cancer cells via EMT or ii) revert their invasive, mesenchymal phenotype into epithelial phenotype (MET) by upregulation of CDH1 expression. High throughput screening of >43 000 LMW compounds, followed by compound design and optimisation in vitro led to the identification ten candidate therapeutic compounds. These compounds displayed significant inhibitory effects on cancer cell invasion (>80%) and induced E-cadherin (re)expression, most likely through the interfere with the binding of transcriptional repressors to the CDH1 E-box elements. We identified a unique compound, OCD155, can effectively and dose-dependently block the acquisition of an invasive phenotype in osteotropic prostate and breast cancer cells (PC-3M-Pro4luc2 and MDA-MB-231/Bluc). When tested in our in vivo models of prostate and breast cancer bone metastasis, treatment of mice with OCD155 strongly and dose-dependently inhibited skeletal metastasis (number of metastases, tumour burden) according to preventive and curative protocols. At the dosages tested, no adverse effects of OCD155 were observed (body weight and liver toxicity parameters). To the best of our knowledge, our studies are the first to demonstrate the efficacy of new small molecule EMT inhibitor in the treatment of experimental skeletal metastasis.
Disclosure: The authors declared no competing interests. This research was supported by the EU Framework 6 PRIMA and the International Innovation Program PRONET Agentschap.nl).