Technology to Unmask Accessible Tumor Vascular Targets

描述（由申请人提供）： 此拨款申请建议应用创新，（无论是一个良好的测试集 或经过良好测试的集），但经过合理测试的技术集，以定义 血管内皮细胞表面的蛋白质组， 发现正常血管和肿瘤血管之间的蛋白质差异。多 抗癌研究的重点是肿瘤细胞靶向药物的开发 这些疗法在破坏生长在肿瘤细胞中的肿瘤细胞方面非常有效， 培养皿中，但不是当注射到病人？的血流，因为 各种屏障阻止进入肿瘤内的癌细胞。一个 实体瘤治疗的有吸引力的替代策略是靶向 肿瘤血管中固有的内皮细胞 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，因为目标不是预防肿瘤， 血管生长，而是肿瘤特异性破坏。的新成员 从我们最近的工作中可以明显看出，血管靶向策略 在内皮细胞中发现的囊泡转运途径（小窝）， 选择性地克服这种关键细胞屏障，以允许在细胞内递送。 组织.直接发现肿瘤血管靶点现在是可行的，因为 新技术，我们已经开发出，以促进分子映射 内皮细胞表面及其小窝，因为它们天然存在于 组织.在这里，我们将尝试第一次深入的抗体和蛋白质组学 大鼠肺血管内皮细胞表面及其小窝的分析 肿瘤使用新的组织亚分级技术，比较一个-和 二维凝胶电泳和质谱分析。数据 只要证明这种新方法在揭示 在多种大鼠，小鼠， 兔子、猴子和人类肿瘤。对此类候选物特异的抗体 将产生目标，以建立针对 肿瘤、内皮和小窝，以及测试肿瘤免疫靶向， vivo.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递送，克服内皮细胞 屏障，并最终提供改善的局部肿瘤治疗， 对旁观者器官的伤害发现肿瘤血管靶点可能是有用的 改善人类实体瘤的早期检测和治疗。

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.