Abstract 1510: Improving replication kinetics by using a single shRNA p21/Waf-1 construct in backbone of prostate specific CRAd

Abstract

Abstract Conditionally replicating adenoviruses (CRAds) represent a promising modality for the treatment of neoplastic diseases, including Prostate Cancer. Selectively replicative viruses can be generated by placing a tissue or cancer-specific promoter upstream of one or more of the viral genes required for replication (e.g., E1A, E1B). We have previously reported the attenuated replication of these viruses by multiple cellular mechanisms. In this study we investigated the importance of p21/Waf-1, a cdk inhibitor on viral replication and tumor growth. Using RNA interference against p21/Waf-1 in prostate cancer cells we demonstrated an increase viral replication and viral oncolysis of the prostate cancer cells. Similarly CRAd viruses that carry p21/Waf-1 shRNA (Ad5-RV004.21) were able to prevent tumor outgrowth by inhibiting growth of established tumor xenografts that resulted in a marked increase in the mean survival time of tumor-bearing mice compared to CRAd with out p21/Waf-1shRNA (Ad5-RV004) or mock treated control groups. Furthermore in combinatory studies of Ad5-RV004.21 with Adriamycin a supra-additive effect was observed only in CRAds viruses that harbor shRNA against p21/Waf-1. Taken together these findings of enhance viral replication in prostate cancer cells by using RNA interference against the cdk inhibitor (p21/Waf-1) have significant implications in the development of prostate-specific CRAd therapies. 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 1510.