NEOVASCULATURE TARGETING OF SPONTANEOUS SOLID TUMORS

该项目的主要重点是在实体瘤供血的小血管内皮细胞表面识别肿瘤诱导蛋白，并创建和表征潜在的诊断和治疗探针，这些探针可能有助于改善实体瘤的早期发现和治疗。我们将主要关注我们目前最有希望的候选肿瘤、内皮和小泡特异性蛋白AnnA1的特征，该蛋白通过我们对肿瘤管腔内皮细胞膜的蛋白质组学分析鉴定出来。我们的目标是使用我们针对AnnA1的抗体小组来实现对其体内肿瘤靶向潜力的详细评估，并收集必要的关键数据来定义合理

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.