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To support rapid growth, tumors need to synthesize lipids and cholesterol, and stopping production of these metabolites can inhibit tumors. Statins are among the most prescribed and well-tolerated drugs in the world to treat cardiovascular disease by inhibiting cholesterol synthesis. Statins are known to be toxic to cancer cells and have attracted renewed attention because of the increased appreciation of the importance of the regulation of metabolism in tumors. Statins have not progressed beyond clinical trials because some patients significantly benefit, while others do not in a range of cancers. Our strategy is to improve our understanding of the mechanisms of tumor responses to statins and thereby enhance statin toxicity to cancer cells. We have found that combining statins with oxysterols synergistically enhances statin toxicity by 10-fold. Oxysterols are oxidized cholesterol metabolites that naturally occur during cholesterol synthesis. We hypothesize that oxysterols inhibit the expression of cholesterol synthesis through a master regulator of metabolism, SREBP-2, making cells more sensitive to statins. We find that oxysterols enhance statin induced apoptosis and suppress the expression of SREBP-2 along with SREBP-2 targets including HMGCR. We have tested a number of oxysterols that work with a range of efficacies in seven representative ovarian cancer cell lines. P53 status is not a major factor in mediating oxysterol activity. Oxysterols inhibit expression of SREBP-2 leading to lower expression of the statin target, HMGCR, along with lower expression of most of the mevalonate and cholesterol biosynthesis pathways. These observations suggests that the cell's response to statins and not initial expression levels may be most critical to determine which patients may benefit from statin therapy. Current studies are testing the combination in mouse models and evaluating the function and regulation of SREBP-2 in ovarian cancer. In summary, we have discovered an approach to suppress cancer cell's response to statins leading to greatly improved statin efficacy highlighting the importance of the mevalonate and cholesterol pathways in mediating growth and survival. Citation Format: Cinzia Casella, Alexander S. Brodsky. New approaches to target mevalonate biosynthesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A40.