Abstract 3789: Targeting cholesterol biosynthesis pathway to inhibit growth of drug resistant ovarian cancer cells
Authors: Liang Yayun , Aebi Johannes , Nephew Kenneth , Hyder Salman M. 
Published: July 2016

Despite concerted efforts to develop new strategies for preventing and treating ovarian cancer, almost 25,000 new cases of the disease are reported each year in the United States. Cancers of the ovary have poor prognosis due to drug resistance and metastasis, and have the highest mortality rate of all the known gynecological malignancies. Standard treatments include systemic high-dose toxic chemotherapeutic drugs but drug-resistance almost always occurs. Consequently novel and more effective non-toxic therapies for ovarian cancer are urgently needed. The biosynthetic pathway leading to cholesterol production is an attractive therapeutic target since cholesterol is an essential structural and functional component of cell membranes required for tumor growth. Therapy with statins, a class of cholesterol biosynthesis inhibitors that target HMGCoA-reductase, is associated with certain undesirable side effects; consequently alternative approaches to inhibit cholesterol biosynthesis are being considered. 2,3-oxidosqualene cyclase (OSC), which converts 2, 3-monoepoxysqualene to lanosterol, has recently emerged as a possible new target for inhibiting this pathway. Since OSC occurs downstream of HMG-CoA reductase during cholesterol biosynthesis, its inhibition is not likely to be associated with the adverse effects caused by statins. Potent small molecule inhibitors of OSC have been identified. While testing anti-cancer properties of one such inhibitor, RO0488071 [4′-[6-(Allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate]) (RO), we found in short-term assays (24 h) that pharmacological doses very effectively reduced the viability of drug-resistant ovarian tumor cells (SK-OV-3 and OVCAR-3), determined by Sulforhodamine B colorimetric assay. In long-term assays (7 days), nM concentrations of the drug were also effective. Importantly, RO (20-40 mg/kg/day; ip) significantly suppressed tumor xenografts obtained with ovarian cancer cells (SK-OV-3; 336 ± 60 mm3 vs 171 ± 20 mm3) with no toxicity to experimental animals (27 treatments once tumors reached 100 mm3). Interestingly, RO elevated levels of the anti-proliferative protein estrogen receptor β (ERβ)in tumor cells in vitro. Initial studies suggest that a combination of RO and an ERβ agonist, enhances the antiproliferative effects of RO in ovarian cancer cells in an additive or synergistic manner. Our study is the first to demonstrate that disrupting cholesterol biosynthesis by inhibiting OSC is a novel and potent means by which to suppress growth of human ovarian cancer cells. Further studies will determine whether combining RO with ERβ agonists is an even more effective therapeutic approach to treat drug-resistant ovarian cancer in vivo.

Support: Peer-reviewed COR faculty grant from the College of Veterinary Medicine, and by generous funds from the donors to the Ellis Fischel Cancer Center, University of Missouri-Columbia.

Citation Format: Yayun Liang, Johannes Aebi, Kenneth Nephew, Salman M. Hyder. Targeting cholesterol biosynthesis pathway to inhibit growth of drug resistant ovarian cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3789.