The mortality associated with prostate cancer is primarily due to systemic dissemination of the disease to which conventional therapies such as surgery, androgen-depletion and chemotherapy fail to provide long-term cure. Thus, development of novel approaches is important for the treatment of both primary and metastatic prostate disease. Among the possible therapeutic targets, the tumor endothelium appears promising since endothelial cell growth during angiogenesis is crucial for tumor growth and metastasis. A majority of earlier studies using purified anti-angiogenic factors to modulate disease have been unsuccessful due to a requirement for constant administration, clinical side effects, and/or high cost. Thus, gene therapy approaches to achieve stable expression of anti-angiogenic factors in vivo have the potential to overcome many of these limitations. Recombinant adeno-associated virus (rAAV) vectors are a unique group of viruses that are less immunogenic than other viral vectors and arc integrating, hence, have greater advantage for long-term expression. We have recently shown that genetic transfer of an anti-angiogenic factor, sFlt-I abrogated the growth of human fibro sarcoma in nude mice. We also demonstrated with targeted-vectors, that high-efficiency, tumor cell-specific delivery is achievable. Further, by generating a genetically deficient transgenic adenocarcinoma mouse prostate cancer (TRAMP) model for the early growth response protein-I (Egr-l), we recently demonstrated a role for Egr-1 in delaying the progression of prostatic intra-epithelial neoplasia(PIN) to invasive carcinoma. Additional preliminary studies with rAAV encoding the anti-angiogenic factors human angiostatin, endostatin and sFlt-1 have shown protection against the growth of a human epithelial ovarian tumor cell line in athymic mice indicating the efficacy of AAV-mediated anti-angiogenic gene therapy. Based on these results, we hypothesize that gene therapy for prostate Cancer by AAV-mediated stable expression of anti-angiogenic factors will be efficacious both as a primary therapy, and as an adjuvant. Further, development of prostate cancer-specific rAAV containing anti-angiogenic genes would not only increase targeted-transduction but also minimize the vector dose and thus any associated toxicities. The present proposal will determine the efficacy of sustained anti-angiogenic gene therapy both as a primary therapy, and as an adjuvant therapy against recurrence in the TRAMP model. A successful outcome of these studies will form the basis for the development of Phase I clinical trials.
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