Although limitations regarding the delivery and targeted expression of potentially therapeutic genes remain, it is important to continue to work toward effective cancer gene therapy including gene therapy for prostate cancer. We have previously developed in situ adenoviral vector-mediated gene therapy for HSV-tk+GCV gene therapy. More recently, we have continued with more immunomodulatory gene therapy based approaches and a Phase I clinical trial involving adenoviral vector-delivered IL-12 gene therapy in patients with prostate cancer is pending. We recently identified a gene, RTVP-1 (related to testes-specific vespid and pathogenesis proteins), that possessed direct cytotoxic and immunomodulatory activities that could offer unique opportunities for specific gene therapy approaches. We have recently demonstrated that mouse RTVP-1 (mRTVP-1) is a direct p53 target gene and is upregulated by p53 in mouse and human prostate cancer cells. Further analysis revealed that RTVP-1 mRNA is abundant in normal mouse and human prostatic epithelial cells, but is progressively downregulated in primary tumors and has only low-level expression in metastatic tissues. In an orthotopic mouse model of metastatic prostate cancer adenoviral vector-mediated mRTVP-1 (AdmRTVP-1) expression leads to apoptosis, potent growth suppression, anti-angiogenic and antimetastatic activities, and importantly local and systemic immune response. We propose to conduct further preclinical studies to develop optimized adenoviral vector systems for RTVP-1 gene therapy. We will also evaluate specific RTVP-1 gene-modified cell-based strategies including RTVP-1 gene-modified tumor cell vaccines. We have considerable experience with alternative promoters for adenoviral vectors and will fully evaluate non-specific promoters such as CMV relative to a prostate selective promoter such as ARR2PB and a prostate cancer/endothelium targeting promoter (caveolin-1) in replication-defective and attenuated replication competent adenoviral vector systems. These preclinical studies will proceed concurrently with the initiation of a Phase I trial in which replication-defective adenoviral vectors will be used to transfer the human RTVP-1 gene directly into prostate cancer in patients who will subsequently be subjected to radical prostatectomy. Comprehensive analysis of the effects of RTVP-1 locally and systemically will be completed in this clinical trial.
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