The broad focus of this project is to identify tumor-induced proteins on the blood-accessible endothelial cell surface on the small blood vessels feeding solid tumors and to create and characterize potential diagnostic and therapeutic probes that may prove useful in improving the early detection and treatment of solid tumors. We will focus primarily on characterizing our currently most promising candidate tumor-, endothelial-, and caveolae-specific protein, AnnA1, identified through our proteomic analysis of tumor luminal endothelial cell plasma membranes. Our goal is to use our panel of antibodies targeting AnnA1 to achieve a detailed evaluation of their tumor targeting potential in vivo and to gather critical data necessary to define rational therapeutic strategies using our novel caveolae targeting strategy. To this end, we will utilize each of the cores (imaging, intravital microscopy, and biostatistics) as well as collaborate with other PPG projects to address the following specific aims: 1. To use our new antibodies specific for AnnA1 to image AnnA1 expression, tumor targeting, and processing in vivo in multiple spontaneous mouse models of primary and metastatic lesions-of breast tumors. 2. To investigate the role of AnnA1 expression on endothelial cell proliferation and tumor growth. 3. To test the ability of AnnA1 antibodies to target drugs specifically to the vascular endothelium in primary and metastatic lesions of spontaneous transgenic mouse tumor models by assessing the bioefficacy of immunotoxins and radio-immunotherapy in vivo. We will use multiple biochemical and microscopic methodologies to examine in vivo and in cell culture the role AnnA1 expression, externalization, and localization to caveolae on tumor biology (i.e. growth and progression). Tumor processing of the AnnA1 antibodies will be visualized at the whole body, tissue, cell, and subcellular levels in order to ascertain the pathway and final destination of delivery in vivo as well as evaluate possible caveolae transport across the tumor endothelium and uptake by the underlying cancer cells. With this information, it appears possible to develop diagnostic and imaging agents to detect and stage solid tumors and, more significantly, elaborate useful strategies for more effective and less toxic anti-cancer treatments.
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