Abstract 4602: Cholesterol and ezetimibe: Effects on tumor growth and survival outcomes: An interim analysis

Introduction and Objectives: Prostate cancer (PC) is affected by cholesterol metabolism and cholesterol-mediating medications. Ezetimibe, a gut cholesterol-uptake inhibitor, inhibits angiogenesis in human PC xenografts when given as preventive therapy. We investigated the effect of ezetimibe on PC growth when given as treatment therapy.Methods: We randomized 125 SCID mice into three initial diets: a high-fat, low-cholesterol diet (HFLC) (40% fat, 43% carbohydrates, 17% protein, 0.21% cholesterol), a high-fat, high-cholesterol diet (HFHC) (40% fat, 43% carbohydrates, 17% protein, 1.25% cholesterol), and a high-fat, high-cholesterol diet supplemented with ezetimibe (30mg/kg) (HFHC+Z). Mice were fed ad libitum. After two weeks, we injected 106 LNCaP cells into the flanks, with 5-10 mice/group serving as non-injected controls. At two weeks post-injection, half the injected and control mice in the HFHC diet group had ezetimibe added to their diet (HFHC+delayed Z). Tumor volumes and body weights were measured twice weekly. Mice were sacrificed once tumors reached 1000mm3. Body weights and tumor volumes were compared across groups using Kruskal-Wallis test. Interim survival outcomes for this on-going study up to 86 days post-injection were evaluated with Cox proportional hazards.Results: At 1 day prior to injection, there were no significant differences in body weights across groups. At post-injection day (PD) 2, HFHC+Z mice with tumors were significantly lighter vs. all other mice (p=0.009). By PD 21, HFHC+delayed Z mice with tumors also became significantly lighter vs. the HFLC and HFHC mice with tumors (p<0.001). At PD 86, all mice with tumors were significantly lighter than their control counterparts without tumors (all p<0.013). Tumor volumes were not significantly different across groups (p=0.280). Likewise, survival was not significantly different across groups at PD 86 (p=0.125).Conclusion: Preliminary evidence from this on-going study demonstrates that ezetimibe is associated with weight loss, but only in mice with PC xenografts. The administration of ezetimibe as preventive vs. treatment therapy does not appear to affect tumor growth or survival. Future studies to explore the interplay between cholesterol metabolism and PC include comparing serum levels of cholesterol, insulin, IGF-1, and IGFBP-3, and tumor markers of proliferation and angiogenesis including akt, pakt, mTOR, VEGF, HIF, CD31 (microvessel density) and ki67 (proliferation). Moreover, we are continuing to follow the mice for any differences in tumor growth or survival.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4602. doi:10.1158/1538-7445.AM2011-4602

Duke Scholars

Author Salvatore Vincent Pizzo Pathology