Abstract 4711: Silencing of miR-221 with anti-microRNA oligonucleotides is an effective therapeutic for hepatocellular carcinoma

Abstract Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis as there are no standardized therapies to treat this stage of the disease. Inhibition of microRNAs that are overexpressed in the tumor with antisense oligonucleotides represents a novel option to treat HCC. For antisense oligonucleotides to be effective, they must reach the target tumor tissue, inhibit the miRNA, modulate the miRNAs target protein levels and prolong survival. We evaluated anti-miR-221 in normal and tumor bearing mice. Of eight different chemistries evaluated, the cholesterol labeled, 2’ O methyl, phosphorothioate modified anti-miR-221 (chol-anti-miR-221) was the most effective at reducing proliferation in vitro. In the absence of transfection reagents, the in vitro proliferation was reduced by the chol-anti-miR-221 but not the scrambled control. Non specific toxicity was observed in vitro for each of the chemically modified scrambled control oligos when transfected with lipid reagent. Chol-anti-miR-221 had improved pharmacokinetics and liver tissue distribution compared to the non cholesterol labeled oligonucleotide in C57Bl/6 mice. Endogenous miR-221 levels in the liver were reduced by chol-anti-miR-221 in C57Bl/6 mice by 90%, 7 days following the start of the dosing schedule. In situ hybridization demonstrated that chol-anti-miR-221 accumulated in the tumor cells of orthotopic mice. Chol-anti-miR-221 reduced endogenous miR-221 levels in the tumors of orthotopic xenograft mice by > 95% and increased p27Kip1 target protein by 3-fold, 7 days after dosing. Chol-anti-miR-221 produced a survival advantage in orthotopic mice compared to those mice treated with a scrambled control oligo (P < 0.05). Our data demonstrate that chol-anti-miR-221 is efficacious in an orthotopic mouse model of HCC and suggests that such a therapy may be beneficial in patients with advanced HCC. 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 4711. doi:10.1158/1538-7445.AM2011-4711