Prostate-Specific and Tumor-Specific Targeting of an Oncolytic HSV-1 Amplicon/Helper Virus for Prostate Cancer Treatment

摘要

Oncolytic virotherapy is a promising approach for treating advanced cancers. A major focus in developing oncolytic viral vectors is enhancement of tumor-specificity and reduced toxicity to normal tissues. Recently discovered microRNAs (miRNAs) have provided a new opportunity for more stringent regulation of tumor-specific viral replication. In the present study, we incorporated multiple copies of miRNA complementary target sequences (for miR- 143 or miR-145) into the 3' untranslated region (3'UTR) of a herpes simplex virus-1 (HSV-1) essential viral gene, ICP4, to create CMV-ICP4-143T and CMV- ICP4-145T amplicon viruses. Our results indicated that while miR-143 and miR- 145 are highly expressed in normal tissues, they are significantly downregulated in prostate cancer cells. We further demonstrated that miR-143 and miR-145 inhibited the expression of the ICP4 gene at the translational level by targeting the corresponding 3'UTR in a dose-dependent manner. This enabled selective viral replication in prostate cancer cells. When mice bearing LNCaP human prostate tumors were treated with these miRNA-regulated oncolytic viruses, a >80% reduction in tumor volume was observed with significantly attenuated virulence to normal tissues in comparison to control amplicon viruses not carrying these 3'UTR sequences. Our study is the first to show that inclusion of specific miRNA target sequences into the 3'UTR of an essential HSV- 1 gene is a viable strategy for restricting viral replication and oncolysis to cancer cells while sparing normal tissues.