Explore the anticancer and antimetastatic effect of soluble epoxide hydrolase inhibitors (sEHI) in the treatment of human uveal melanoma (UM) in 2d and 3d cell culture models

Abstract

Uveal melanoma is the primary form of eye cancer– a rare but deadly disease with up to 50% of the patients’ died from metastasis. Patients with metastatic UM have a lifespan of up to 18 months. There are few proven pharmacological treatments for UM, which are associated with suboptimal clinical outcomes. The pathogenesis of UM is largely unknown, which greatly limited the progress of UM drug discovery. This project is to screen novel candidate drugs from a group of kinase inhibitors for the treatment of UM, which will address the unmet need to treat this rare but deadly cancer. Soluble epoxide hydrolase (sEH) is a key enzyme involved in fatty acid metabolism, which is involved in cell mitochondrial function. Its inhibitors have been shown to exhibit anti-cancer effect; however, little is known regarding their applications in the treatment of UM. This study screened the anti-cancer and anti-metastatic effect of a group of in-house synthesised epoxide hydrolase inhibitors (sEHIs) in UM cell lines. UC2288 is the lead molecule selected from this compound library due to its potent effect in reducing cell viability in UM cell lines. Further molecular assays have been performed to evaluate the anti-UM effect of this lead molecule in both 2D and 3D UM cell culture models. The findings in this study indicated that 2288 is a novel drug candidate for UM, which shall be further investigated in in vivo settings.