ANTI-ANGIOGENESIS GENE THERAPY FOR DE NOVO TUMORS

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Angiogenesis is an essential component of tumor progression during which new blood vessels nourish growing tumors and facilitate rapid tumor expansion. Recently, two angiogenesis inhibitors (AngIs), angiostatin and endostatin, were isolated from human tumor xenografts in mice by the Folkman lab (Harvard). These proteins inhibit endothelial cell proliferation and are effective inhibitors of xenograft tumor growth when introduced into mice subcutaneously. Such tumors do not appear to develop resistance to these factors, suggesting that they could provide effective long-term therapy against cancer. However, more extensive preclinical experimentation is required to address several important issues. For example, the xenograft models represent an artificial experimental system, since cell lines are used to tumors subcutaneously in the mouse. Treatment of such tumors may not reflect the response of de novo tumors arising in natural sites. Assessment in genetically altered mice where tumors arise de novo is the next step in testing the efficacy of this approach. Another problem has been in the difficulty in isolating enough active factor for even the mouse studies, making human clinical studies challenging. Somatic delivery of the genes encoding these factors would circumvent the need to produce large quantities of purified protein. This proposal aims to test the efficacy of somatic gene delivery by adeno-associated virus (AAV) and adenovirus (ad) vectors into well-characterized de novo transgenic mouse tumor models. The approach will also be extended to at least one additional AngI, an active thrombospondin-1 fragment. The specific aims are to: (1) Characterize and optimize somatic delivery of recombinant AAV and ad vectors (rAAV) carrying the AngI genes to mouse muscle and liver for secretion to serum, and to brain and mammary tissue; (2) Test the therapeutic efficacy of genetic therapy (GT) with AngIs in a well characterized choroid plexus brain tumor model that undergoes a consistent transition to angiogenesis; (3) Test AngI GT in a non-CNS metastatic mammary tumor model using approaches similar to those in aim 2.