Abstract 2821: Cholesterol and its metabolism impact ovarian cancer progression

Abstract

There is an urgent need to develop new therapeutic or lifestyle strategies for treating ovarian cancer due to its high mortality and recurrence rate. In this regard, we found that cholesterol appears to be clinically important for ovarian cancer survival, highlighting it and its metabolism as potential therapeutic targets for improving the lifespan of patients. In a cohort of 153 patients, we found high total cholesterol or high LDL cholesterol was associated with high tumor grade, which in turn was associated with poor survival. Additionally, patients prescribed cholesterol lowering drugs such as statins, cholesterol absorption inhibitors or fiber were associated with significantly improved overall survival. We did not observe significant differences between statins and other cholesterol lowering drugs, indicating the effects observed were most likely due to cholesterol lowering rather than other unintended pharmacologic properties of statins. Cytochrome P450 enzymes catalyze the first steps in cholesterol metabolism pathways. Among them, CYP27A1 is highly expressed in myeloid cells and oxidizes cholesterol into 27-hydroxychoelsterol (27HC), which is the most abundant oxysterol and an endogenous signaling molecule. Analysis of publicly available databases indicated that low tumoral CYP27A1 expression was associated with better progression-free survival and overall survival. Conversely, high tumoral CYP7B1 expression, the enzyme that metabolites 27HC, was associated with improved progression-free survival. Therefore, we hypothesized that CYP27A1/27HC might be mediating the effects of cholesterol on cancer survival. Indeed, we found ovarian tumors failed to grow in CYP27A1−/− mice, eventually completely regressing, while treatment with exogenous 27HC was able to sustain tumor growth in CYP27A1−/− mice, indicating that CYP27A1/27HC are important for ovarian cancer progression. Analysis of tumors and lymphoid tissues suggested that 27HC was associated with compromised immunosurveillance. Specifically, CYP27A1/27HC-axis altered the recruitment of 1) monocytic-MDSCs, an immunosuppressive subtype of myeloid cells, 2) antigen-presenting myeloid cells, and 3) CD4+ T cells. Thus, the CYP27A1/27HC-axis presents an alternative path for cancer associated immunosuppression, offering a potentially novel therapeutic target. We tested the therapeutic utility of targeting this axis and found that a small molecule CYP27A1 inhibitor significantly improved the efficacy of anti-PDL1 checkpoint inhibition in a preclinical model. Collectively, our data suggest that cholesterol/27HC-axis modulates the ovarian tumor microenvironment and promotes cancer progression, revealing a novel therapeutic target for the treatment of ovarian cancer. Supported by: NIH R01CA234025 (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, Georgina Cheng, Edward Roy, Marta Spain, Ronald Kimball, Nikolas Snyder, Melina Salgado, Debby Vannoy, Betsy Barnick, Liqian Ma, Varsha Vembar, Anna Vardanyan, Amy Baek, Joanna Burdette, Erik R. Nelson. Cholesterol and its metabolism impact ovarian cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2821.