Abstract 199: Host CYP27A1 expression is essential for ovarian cancer progression

Abstract

Abstract Ovarian cancer continues to have a high mortality and recurrence rate. Hence, there is an urgent need to develop new therapeutic or lifestyle strategies. In this regard, epidemiological studies have implicated elevated cholesterol as a negative prognostic factor. Conversely, ovarian cancer patients prescribed cholesterol lowering drugs (HMGCoA-R inhibitors; statins) exhibit significantly increased progression free survival (PFS). Therefore, cholesterol appears to be clinically important for the progression of ovarian cancer. Considering the potential mechanisms by which cholesterol impacts ovarian cancer progression, it was noteworthy that CYP27A1 encodes the first enzyme in the alternative pathway of cholesterol catabolism, producing 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol that has recently been shown to have the capacity to activate the estrogen receptors and liver x receptors. Our bioinformatics analysis of human tumoral mRNA expression indicated that low CYP27A1 expression was associated with increased PFS. Conversely, high CYP7B1 expression, the enzyme that metabolites 27HC, was associated with increased PFS. Therefore, we hypothesized that CYP27A1 is involved in ovarian cancer pathophysiology via 27HC signaling. To directly investigate the role of CYP27A1 in ovarian cancer progression, we monitored the growth of tumors grafted into the ovarian bursa of wildtype and CYP27A1 knockout (KO) mice. Strikingly, we found that ovarian tumors failed to thrive in CYP27A1 KO mice, eventually completely regressing. Importantly, treatment with exogenous 27HC was able to sustain tumor growth in CYP27A1 KO mice. In exploring the potential mechanisms by which this occurs, we found 27HC had very little effect on ovarian cancer cell proliferation in vitro, however, was associated with the enrichment of certain myeloid populations within tumors. Specifically, treatment with exogenous 27HC significantly enhanced the infiltration of M-MDSCs, while significantly fewer M-MDSCs were found in tumors from CYP27A KO mice. M-MDSCs are a myeloid-immune cell type known to be pro-tumorigenic, at least in part through their suppression of cytotoxic CD8+ T cells. This would suggest that inhibition of CYP27A1 might improve the efficacy of immune checkpoint inhibition. Therefore, we tested the therapeutic utility of combining a small molecule inhibitor of CYP27A1 with anti-PD-L1. Indeed, combining these two approaches significantly decreased ovarian tumor growth in a preclinical model. Collectively, our preliminary data strongly indicate that CY27A1 expression is critical for sustaining ovarian cancer progression and is a viable target in combination with checkpoint inhibition. This work was supported by the NIH R00CA172357 (E.R.N.), a Cancer Scholars for Translational and Applied Research (C*STAR) Award (S.H.) and NIH T32EB019944 (S.H.). Citation Format: Sisi He, Amy E. Baek, Liqian Ma, Joanna Burdette, Erik R. Nelson. Host CYP27A1 expression is essential for ovarian cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 199.