Development of a conditionally replicating pseudorabies virus for HER-2/neu-overexpressing bladder cancer therapy

Abstract

Overexpression of the HER-2/neu oncogene, a frequent molecular event in a variety of cancers including bladder cancer, is associated with tumor progression and poor prognosis. Therapeutic strategies to targeting HER-2/neu-overexpressing cancer cells have shown promise. Pseudorabies virus (PrV), a herpesvirus of swine, may be exploited as an oncolytic agent for human cancer. Herein, we generated a conditionally replicating glycoprotein E-defective PrV mutant carrying glycoprotein D and herpes simplex virus type 1 thymidine kinase genes, which are essential for viral entry and replication, under the transcriptional control of the HER-2/neu promoter. The recombinant PrV, designated YP2, selectively replicated in and lysed HER-2/neu-overexpressing human bladder, mouse bladder, and hamster oral cancer cells in vitro. Notably, YP2 retarded MBT-2 bladder tumor growth in mice by more than 50% and more than half of the mice survived for over 50 days, whereas all the control mice survived less than 30 days. Taken together, our results suggest that YP2 may have therapeutic potential for the treatment of invasive bladder cancer. Furthermore, because HER-2/neu is overexpressed in a broad spectrum of cancers, this conditionally replicating PrV may be broadly applicable.