Abstract 1811: Breaking scaffolds: Targeting paxillin in ovarian cancer

Abstract

Abstract Background Paxillin is a mediator of many cellular processes important for cancer progression. Here, we characterize the clinical and biologic significance of paxillin in epithelial ovarian cancer. Methods Paxillin and phospho-paxillin expression was determined in 93 human epithelial ovarian cancer specimens. Clinical data were extracted and associations tested using univariate and multivariate analyses. The effect of paxillin silencing on ovarian cancer cell migration and invasion was evaluated in vitro. In vivo paxillin silencing was achieved with siRNA incorporated into DOPC nanoliposomes and its effect on tumor growth, angiogenesis, and proliferation were examined. Results Examination of 93 epithelial ovarian cancers revealed moderate to high paxillin expression in 84% and high phospho-paxillin expression in 63% of tumors. High paxillin expression correlated with high tumor grade (p=0.02) and advanced stage (p=0.03). Phospho-paxillin expression was associated with high tumor grade (p=0.01), suboptimal cytoreduction (p=0.01), and decreased overall survival (p<0.001). Compared to non-transformed ovarian epithelial cells (HIO-180), paxillin expression was increased in chemosensitive (HeyA8, SKOV3) and chemoresistant (HeyA8-MDR, SKOV3-TR) ovarian cancer cell lines. Paxillin siRNA resulted in >85% reduction in protein expression in these cell lines. In vitro paxillin silencing decreased HeyA8 and HeyA8-MDR cell migration (60% and 75%) and invasion (55% and 47%). In orthotopic mouse models, paxillin siRNA treatment reduced tumor growth in HeyA8 and HeyA8-MDR by 49% and 31%, respectively, compared to non-targeting siRNA controls. The greatest efficacy was observed by combining paxillin siRNA with docetaxel, resulting in a >90% and 45% reduction in tumor burden over non-targeting siRNA in HeyA8 and HeyA8-MDR tumors, respectively. The dramatic in vivo effects of paxillin silencing are due, in part, to its activation of multiple signaling cascades once localized to the focal adhesion complex. Protein complex immunoprecipitation confirms interactions with Src, FAK, and EphA2 tyrosine kinases as well as effector molecules such as Crk. Paxillin silencing resulted in decreased proliferation by 57%, decreased microvessel density by 72%, and increased apoptosis by 140% in HeyA8 tumors. Conclusion Paxillin is overexpressed in epithelial ovarian cancer. Paxillin influences several pathways important to cancer progression and represents a novel and attractive treatment target in ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1811.