The Principal Investigator seeks advanced training in a mentored environment to study the role of key mediators of vessel formation and remodeling, angiopoietins-1 and -2 (Ang-1, Ang-2), in the development of vasculature in Wilms tumor. The first objective is to provide an environment for the PI, with his sponsor, Dr. Darrell Yamashiro, so that he may obtain the training in formal courses and at the laboratory bench that is needed for his development into an independent investigator. The second objective is to dissect the role of the angiopoietins in modulating the properties of Wilms tumors, using an orthotopic, metastasizing murine model of human Wilms tumor. Previous work suggests that specific features of tumor vasculature, including sprouting of new capillaries, recruitment of vascular mural cells, and endothelial integrity, are directly regulated by Ang-1 and Ang-2. In addition, angiopoietins may play a key role in the response to chronic VEGF antagonism, a novel therapeutic strategy that is extremely effective in short-term inhibition of Wilms tumor xenograft growth and metastasis. In our pilot studies, Ang-2 is highly expressed in the rapidly sprouting vasculature of Wilms tumor xenografts. When these are exposed to potent VEGF blockade, however, surviving vessels express only Ang-1, and display features linked to expression of Ang-1 (increased caliber, mural cell recruitment, enhanced integrity). Thus, we propose two specific aims: 1. We hypothesize that Ang-1 and Ang-2 play a critical role in forming vasculature with specific features in Wilms tumor. We will test this by over-expressing Ang-1, Ang-2, and a soluble form of their common Tie-2-Fc receptor in the xenograft model, and characterizing effects on vessels (endothelial/mural cell status, arterial/venous specification, and expression of angiogenesis-related genes). We will also examine the effect of these genes on the status of signaling pathways implicated in endothelial proliferation and integrity. 2. We hypothesize that angiopoietin status critically affects Wilms tumor response to VEGF blockade. We will test this by examining changes in Ang-1 and Ang-2 expression during inhibition of VEGF. We will then test the effect of superimposing VEGF blockade on Wilms tumor xenografts that overexpress these genes. Ultimately, we seek to understand the role of angiopoietins in Wilms tumor, with the goal of devising new treatments for children with aggressive cancers.
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