Targeting Prostate Cancer for Gene Therapy Utilizing Lentivirus and Oncolytic VSV Virus

Prostate cancer is the most commonly diagnosed non-skin carcinoma and one of the leading causes of cancer related mortality of men in western society. Approximately half of all men with clinically localized disease are not cured by surgery or radiotherapy. Presently there are no therapies available for advanced and metastatic prostate cancer, thus the emergence of new targeted therapies are urgently required. This project aims to provide a proof of- principle that lentivirus can be engineered to infect cells in a tumor-specific fashion. Additionally, mutated form of Vesicular Stomatitis Virus (VSV), an oncolytic virus capable of replicating in interferon (IFN) response defective cells was used to selectively target prostate cancer cells in vivo. Initially, we looked at the safety and efficacy of interferon-sensitive VSV (AV3 strain) treatment of prostate tumors that arise in situ in immunocompetent, transgenic prostate-specific PTEN-null (PTEN -/-) mice. Prostates of PTEN -/- and control mice were injected with 5x108 pfu/ml of VSV(AV3), which expresses luciferase, and monitored for luminescence over a 96 h time period. Although virus quickly dispersed throughout the bodies of mice after only 3 h, it persisted in the prostate tumors of PTEN -/- mice up to 72 h; while viral distribution rapidly dissipated by 48 h in the control mice. This data was confirmed by plaque assay which showed a higher concentration of replicating virus in prostates of PTEN -/- mice while sparing normal cells in control mice. Our results indicated that direct injection of VSV (AV3) intra-prostaticaly lead to selective infection, replication, and overall increase in apoptotic cell death in malignant tissue while sparing normal tissue due to a faulty IFN response. The original document contains color images.