Targeting orphan nuclear receptor TR3/Nur77 for tumor angiogenesis

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 DESCRIPTION (provided by applicant): Angiogenesis is critical for solid tumor growth beyond minimal size. We have demonstrated that orphan nuclear receptor TR3 (mouse homolog Nur77) transcription factor plays critical roles in tumor angiogenesis. Tumor growth and angiogenesis induced by VEGF-A, histamine and serotonin are almost completely inhibited in Nur77 knockout mice. However, Nur77 null mice are viable, fertile, develop an apparently normal adult vasculature and have no defect in normal skin wound healing. Together these findings suggest that TR3/Nur77 is required for pathological angiogenesis, but not for developmental or physiological angiogenesis, and render it a potentially useful target for anti-angiogenic therapy. We also found that retroviruse expressing TR3/Nur77 siRNA almost completely inhibits the angiogenesis induced by VEGF-A in a Matrigel angiogenesis assay in vivo. In the present proposal, we will identify biomolecules that target TR3/Nur77 to inhibit tumor growth and metastasis. In specific Aim, we will determine whether tumor growth and metastasis can be inhibited by targeting TR3/Nur77. This research will identify siRNA and peptides that could have potential in anti-angiogenic therapy for cancer, providing evidence that a transcription factor can be targetable. This application has translation potential.