Data from Silencing Survivin Splice Variant 2B Leads to Antitumor Activity in Taxane-Resistant Ovarian Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> To study the role of survivin and its splice variants in taxane-resistant ovarian cancer.</p><p><b>Experimental Design:</b> We assessed the mRNA levels of survivin splice variants in ovarian cancer cell lines and ovarian tumor samples. siRNAs targeting survivin were designed to silence all survivin splice variants (T-siRNA) or survivin 2B (2B-siRNA) <i>in vitro</i> and orthotopic murine models of ovarian cancer. The mechanism of cell death was studied in taxane-resistant ovarian cancer cells and in tumor sections obtained from different mouse tumors.</p><p><b>Results:</b> Taxane-resistant ovarian cancer cells express higher survivin mRNA levels than their taxane-sensitive counterparts. Survivin 2B expression was significantly higher in taxane-resistant compared with -sensitive cells. Silencing survivin 2B induced growth inhibitory effects similar to silencing total survivin <i>in vitro</i>. In addition, survivin 2B-siRNA incorporated into DOPC (1,2-dioleoyl-<i>sn</i>-glycero-3-phosphocholine) nanoliposomes resulted in significant reduction in tumor growth (<i>P</i> < 0.05) in orthotopic murine models of ovarian cancer, and these effects were similar to T-siRNA-DOPC. The antitumor effects were further enhanced in combination with docetaxel chemotherapy (<i>P</i> < 0.01). Finally, we found a significant association between survivin 2B expression and progression-free survival in 117 epithelial ovarian cancers obtained at primary debulking surgery.</p><p><b>Conclusions:</b> These data identify survivin 2B as an important target in ovarian cancer and provide a translational path forward for developing new therapies against this target. <i>Clin Cancer Res; 17(11); 3716–26. ©2011 AACR</i>.</p></div>