As advances are made in identifying the molecular mechanisms of neoplastic growth, it has become apparent that neovascularization plays a key role in development of tumors. To this end, the reliance of tumor progression on active neoangiogenesis, and the identification of numerous factors modulating this process, has provided a rationale for gene therapy as a novel anti-cancer strategy based on eradication of tumors via abrogation of their blood supply. In this regard, it has been suggested that specific delivery of anti-angiogenesis genes to the sites of neovascularization may represent the means to realize therapeutic benefit. On the basis, there is a recognized need for gene delivery vector capable of this specific and selective transduction of tumor vasculature endothelium. Thus, we hypothesize that it will be possible to create genetically modified Ad vectors targeted to tumor vasculature and capable of selective transduction and subsequent eradication of tumor vasculature cells. The first specific aim is to develop targetable adenovirus vector by employing the fiber replacement strategy, which will be capable of targeted gene delivery to the endothelial cells of tumor vasculature The second specific aim will employ this novel vector to demonstrate tumor vasculature targeting in in vivo model of disseminated breast carcinoma. The third specific aim is to is to create the derivatives of this viral vector expressing anti-angiogenic factors and to employ them in stable vector capable of efficient transduction and eradication of tumor vasculature cells. By addressing a key issue which limits the translation of present gene therapy strategies into clinical trials, the development of such a vector system proposed herein would therefore represent a major technical advance in gene therapy for breast cancer. Moreover, such vector would be of great utility in a wider field of gene therapy.
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