NEOVASCULATURE TARGETING OF SPONTANEOUS SOLID TUMORS

该项目的广泛重点是确定在喂养实体瘤的小血管上的血液可及内皮细胞表面上的肿瘤诱导蛋白，并创建和表征可能有助于改善实体瘤早期检测和治疗的潜在诊断和治疗探针。我们将主要集中在表征我们目前最有前途的候选肿瘤，内皮细胞和小窝特异性蛋白，AnnA1，通过我们的肿瘤管腔内皮细胞质膜的蛋白质组学分析确定。我们的目标是使用我们的靶向AnnA1的抗体组来详细评估它们在体内的肿瘤靶向潜力，并收集必要的关键数据来确定合理的治疗方案。 使用我们的新型小窝靶向策略的治疗策略。为此，我们将利用每个核心（成像，活体显微镜和生物统计学），并与其他PPG项目合作，以解决以下具体目标：1。使用我们的新抗体特异性AnnA1成像AnnA1的表达，肿瘤靶向，并在多个自发性小鼠模型的原发性和转移性病变的乳腺肿瘤的体内处理。2.探讨AnnA1表达对内皮细胞增殖和肿瘤生长的作用。3.通过评估免疫毒素和放射免疫治疗的体内生物有效性，检测AnnA1抗体特异性靶向药物在自发性转基因小鼠肿瘤模型原发性和转移性病变中血管内皮的能力。我们将使用多种生物化学和显微镜方法来研究体内和细胞培养中AnnA1表达，外化和定位于肿瘤生物学（即生长和进展）的小窝的作用。 将在全身、组织、细胞和亚细胞水平上观察AnnA1抗体的肿瘤加工，以确定体内递送的途径和最终目的地，并评估可能的跨肿瘤内皮细胞的小窝转运和潜在癌细胞的摄取。有了这些信息，似乎有可能开发诊断和成像剂来检测和分期实体瘤，更重要的是，制定更有效和毒性更低的抗癌治疗的有用策略。

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.