Metastasis is the main cause of prostate cancer mortality each year. However, once metastases develop, effective therapeutic options become limited. Gene-based therapy holds promise for disseminated disease. To achieve successful and effective in vivo gene therapy for recurrent or metastatic disease, a potent and prostate-exclusive gene expression vehicle is required. This NCI supported project has enabled us to refine a highly amplified prostate-specific expression strategy, termed two-step transcriptional amplification (TSTA), and to develop many adenoviral vectors capable of achieving image-guided therapy to treat advanced prostate cancer. Another important discovery made during this investigation is that adenoviral vectors (Ads) are efficiently transported into the lymphatic circulation and they can mediate effective gene transfer to nodal metastases of prostate cancer. More interestingly, our current working hypothesis suggests that the lymphatic dissemination process is not just confined to tumor proximal region but impacts metastasis to distal organs, such as lung, liver and bone. This proposal will expand the prostate-targeted vectorology and evaluate the refined vectors in therapeutic paradigms to treat lymphatic metastases of prostate cancer. Moreover, we will also explore immune-suppressive regimen to extend and augment gene expression. Overall this project attempts to address the targeted expression, vector distribution and immunogenicity of adenoviral vectors. These are all issues that are hampering successful in vivo gene therapy. Our hope is to make progress on these limitations and deliver novel effective gene-based treatment for the lethal stage of prostate cancer. PUBLIC HEALTH RELEVANCE: Prostate cancer has a major impact on the health care system in the US. It is the most common solid tumor in men. The American Cancer Society estimates that there will be ~219,000 new cases of prostate cancer in the United States in 2007 and ~27,000 expected deaths. Recent data suggest that the death rate from prostate cancer is decreasing by 4% per year since 1994, possibly reflecting PSA-related early diagnosis and improvement in treatment. However, among patients who undergo prostatectomy with curative intent, 20 to 30% will suffer from disease recurrence as defined by serum PSA elevation. Recurrent, metastatic disease contributes to the majority of the morbidity and mortality of prostate cancer. Unfortunately, no curative treatment exists for disseminated prostate cancer at this time. To gain ground on the management of this aggressive stage of disease, it would be important to develop potent imaging and therapeutic strategies that can specifically target prostate cancer. Gene-based therapy is a flexible form of treatment that holds promising possibility for disseminated disease. In this proposal, we aim to develop a gene expression-based intervention that would couple imaging and cytotoxic therapy to specifically target disseminated prostate cancer cells in the lymph nodes. The overall objective of our project is to develop this cutting-edge gene therapy technology towards clinical application.