Technology to Unmask Accessible Tumor Vascular Targets

描述(由申请人提供)： 这项拨款申请建议应用创新的(要么是经过良好测试的集合 或经过良好测试的集合)，但还需要定义一组经过合理良好测试的技术 血管内皮细胞表面蛋白质组研究进展 发现正常血管和肿瘤血管的蛋白质差异。大有可为 抗癌研究主要集中在肿瘤细胞靶向药物的开发上 在摧毁生长在体内的肿瘤细胞方面非常有效的治疗方法 培养盘却不是什么时候注射进病人体内的？S因为血液流动 各种屏障阻止进入肿瘤内的癌细胞。一个 实体肿瘤治疗的另一种有吸引力的策略是以 排列肿瘤血管的固有可及内皮细胞 对肿瘤生长至关重要。这种血管靶向策略不同于 目前的抗血管生成疗法，因为其目标不是预防肿瘤 血管生长，而不是肿瘤特异性破坏。一项新增加的 从我们最近的工作中可以明显看出，血管靶向策略是 在内皮细胞中发现的一种囊泡运输途径(小窝) 有选择地克服这一关键的细胞屏障，允许在 组织。直接发现肿瘤血管靶点现在是可行的，因为 我们开发的促进分子图谱绘制的新技术 内皮细胞表面及其凹陷天然存在于 组织。在这里，我们将尝试第一个深入的抗体和蛋白质组学 大鼠肺内皮细胞表面及其小凹的分析 使用新的组织亚分割技术的肿瘤，比较一和 双向凝胶电泳法和质谱分析法。数据是 假设这证明了这种新方法在揭示 在多个大鼠、小鼠、 兔子、猴子和人类肿瘤。针对该候选人的特异性抗体 将生成目标，以确定特定程度的 肿瘤、血管内皮细胞和小凹，以及检测肿瘤免疫靶向 活着。这项工作很可能产生肿瘤特异性血管靶点 促进肿瘤导向的药物输送，克服内皮细胞 屏障，并最终提供改进的局部肿瘤治疗 旁观者器官受损。肿瘤血管靶点的发现可能是有用的 在改善人类实体肿瘤的早期发现和治疗方面。

DESCRIPTION (provided by applicant): This grant application proposes to apply innovative, (either a well tested set or well-tested sets) yet reasonably well tested set of technologies to define the proteome of the vascular endothelial cell surface with emphasis on discovering protein differences between normal and tumor blood vessels. Much anticancer research has focused on the development of tumor cell-targeted drug therapies that are quite effective in destroying tumors cells grown in a culture dish but not when injected into the patient?s blood stream because various barriers prevent access to the cancer cells inside the tumor. An attractive alternative strategy for solid tumor therapy is to target the inherently accessible endothelial cells that line tumor blood vessels essential for tumor growth. This vascular targeting strategy is distinct from current anti-angiogenesis therapies because the goal is not preventing tumor blood vessel growth but rather tumor-specific destruction. A new addition to the vascular targeting strategy apparent from our recent work is the utility of a vesicular transport pathway (caveolae) discovered in endothelium for selectively overcoming this key cell barrier to permit delivery inside the tissue. Direct discovery of tumor vascular targets is now feasible because of novel technology that we have developed to facilitate the molecular mapping of the endothelial cell surface and its caveolae as they exist natively in tissue. Here, we will attempt the first in-depth antibody and proteomic analysis of the luminal endothelial cell surface and its caveolae in rat lung tumors using new tissue subfractionation techniques, comparative one- and two-dimensional gel electrophoresis, and mass spectrometric analysis. Data is provided that demonstrates the utility of this new approach in uncovering novel accessible tumor-induced targets expressed in multiple rat, mouse, rabbit, monkey and human tumors. Antibodies specific for such candidate targets will be generated to establish the degree of specificity for the tumor, endothelium, and caveolae as well as to test tumor immunotargeting in vivo. This work is likely to yield tumor-specific vascular targets that facilitate tumor-directed pharmaco delivery, overcome the endothelial cell barrier and, ultimately, provide improved localized tumor therapy with little damage to bystander organs. Discovery of tumor vascular targets may be useful in improving both the early detection and treatment of solid tumors in humans.