Soft tissue sarcoma is a devastating malignancy involving tumors of putative mesenchymal cell origin. The soft tissue sarcoma five year overall survival rate of 50 percent has been stagnant for the past thirty years. No fundamentally new therapies have been introduced since the inception of doxorubicin multi-drug chemotherapy regimens in the early 1970s. The most frequently encountered genetic mutation in soft tissue sarcoma is alteration in the p53 tumor suppressor gene, which occurs in 30-60 percent of all such tumors. Brisk neovascularization at the sarcoma:normal tissue interface is macroscopically observable and occasionally can even compromise surgical resectability. Large central cores of hypoxic tumor necrosis are seen as these malignancies proliferate and outstrip their blood supply. An emerging awareness about tumor angiogenesis has prompted much interest in exploiting this component of the malignant phenotype as a potential therapeutic target. While little is known about angiogenesis in soft tissue sarcoma, the interrelationship between p53 mutation, tumor hypoxia leading to nitric oxide induction, and vascular endothelial growth factor (VEGF) has prompted the applicant to consider the following specific aims: 1) Investigate the pathobiologic impact of p53 gene mutation on VEGF induction in STS. 2) Examine the molecular mechanisms underlying p53 gene regulation of VEGF in STS. 3) Develop experimental molecular therapeutic approaches that inhibit STS progression by targeting mutated p53 gene and VEGF expression. To address these specific aims, an experimental design will be utilized that incorporates an in depth molecular based examination of the biology and mechanisms underlying p53 induction of VEGF, as well as the role of nitric oxide in this process. Preclinical therapeutic interventions will also be considered utilizing wild-type p53 gene restoration therapy combined with anti-VEGF approaches (antisense VEGF and anti-VEGF receptor monoclonal antibody treatments). Isolated limb perfusion is already accepted as a standard means of delivering high dose chemotherapy to extremity sarcoma. A nude rat human sarcoma xenograft model already established in the applicant's laboratory will be used as a novel means of delivering the above therapeutic constructs directly into human sarcoma xenografts. It is hoped that by successfully completing this project the applicant will enhance our knowledge of the regulatory interaction between p53 and VEGF in soft tissue sarcoma, leading to subsequent clinical trials in humans that will address these molecular derangements, perhaps via novel isolated limb perfusion gene delivery systems.
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