ANGIOGENESIS TARGETS FOR THERAPEUTIC DEVELOPMENT

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DESCRIPTION (provided by applicant): The American Cancer Society predicts that over 1.3 million new cases of cancer will be diagnosed in 2003. With a 5-year relative survival rate at only 62% for all cancers combined, new therapies are clearly needed. Critical to tumor growth and metastasis is the vascularization of the tumor in a process called angiogenesis. Tumor angiogenesis represents a unique biological target for therapeutic development. The long-term goal of this proposal is to develop new therapies that specifically target tumor angiogenesis. Toward this goal, Discovery Genomics, Inc. has identified seven novel genes involved in angiogenesis. The functional roles of these genes were found by injection of antisense morpholino phosphorodiamidate oligonucleotides (MPOs) into zebrafish embryos. The goal of this proposal is to prioritize these angiogenesis targets for future development of therapeutics. In this Phase I SBIR, we propose to use a set of low-cost tests in zebrafish and mouse embryos that will allow us to both validate and functionally annotate high-priority genes. The effects of knockdown of the seven angiogenesis-target genes will be characterized by evaluating their phenotypes with respect to endothelial sprouting and migration. Genes that are required for these processes are proposed to make superior therapeutic targets. For this, ve-cadherin in situ hybridization will be carried out on zebrafish embryos that were injected with MPOs against the seven genes. Endogenous expression profiles will be examined in zebrafish and mouse embryos to determine if the targets have conserved, vascularrelated, expression patterns. The seven genes will also be tested for their ability to promote angiogenesis in an ectopic expression assay in zebrafish. Furthermore, the genes will be tested for their ability to rescue the knockdown phenotypes in MPO-injected zebrafish embryos. If any of the seven genes can promote angiogenesis or rescue the MPO induced phenotypes, the human orthologs of these genes will be tested to establish angiogenesis activity. Based on these tests, the highest priority gene(s) will be used for future testing in mammalian tissue culture and mouse tumor models for development as therapeutics for cancer treatment.