(171f) Analysis of a Natural Compound Therapeutic on Engineered Ovarian Cancer Spheroids

Ovarian cancer the most lethal gynecological cancer with fatality to higher than 70% of patients in 5 years after diagnosis¹. Tumor cells shed from the primary tumor as single or multicellular and form spheroids within the peritoneal cavity². Spheroid formation within patient ascites increase cancer cell resistance against anoikis³and anti-cancer drugs^4,5. The clinical outcome of ovarian cancer has led to the development of three-dimensional (3D) cell culture to study ovarian cancer^6–10. Spheroid models of ovarian cancer has been used to evaluate the effectivity of new anticancer agents^11–13.

Developing precision drugs targeting the proliferation of cancer cell is essential for cancer treatment. Natural product compound OSW-1 offers a novel targeting mechanism for cancer cell proliferation. It targets oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4)^14–18. ORP4 is a known precision target in cancer and essential for cancer cell viability and proliferation^18–20, however, OSBP has no such functionality. OSW-1 has been shown to have a potent cytotoxicity against variety if cancer cell lines in vitro, with an average IC₅₀ of 0.78 nM²¹.

ORP4 is highly expressed in ovarian cancer according to FANTOM database²². Here, we show the cytotoxic activity of ORP-4 targeting OSW-1 in a panel of ovarian cancer cell lines as well as ovarian cancer spheroids. OSW-1 reduced the expression of ORP4 protein both monolayer and spheroids culture and cytotoxic activity of OSW-1 was correlated with ORP4 levels. Removal of lipids in the extracellular environment which is also a feature of limited amounts of exogeneous cholesterol in non-vascularized tumors^23,24, increased the activity of OSW-1. Overall, our results show that natural compound OSW-1 induces cytotoxicity in monolayer and spheroid models of ovarian cancer with a significantly increased effectivity compared to Taxol and Cisplatin and offer a novel path for potential treatment of ovarian cancer.

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