Molecular heterogeneity of tumor blood vessels

肿瘤血管的分子异质性

• 批准号: 6563960
• 负责人: WADIH ARAP
• 金额: $ 29.68万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563960
• 关键词: angiogenesis inhibitors; antineoplastics; biomarker; cardiovascular imaging /visualization; clinical research; collagen; cooperative study; differential display technique; drug screening /evaluation; genetically modified animals; human subject; laboratory mouse; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer classification /staging; neoplastic growth; nonhuman therapy evaluation; peptide library; receptor expression

Description: (provided by applicant) We have developed an in vivo selection system in which phage capable of selective homing to different tissues are recovered from a phage display peptide library following intravenous administration. Using this strategy, we have isolated several peptides that home to normal organs or tumors. We have shown that each of those peptides bind to different receptors that are selectively expressed on the vasculature of the target tissue. The tumor-homing peptides target receptors that are up regulated in tumor angiogenic vasculature. Marked improvement in the efficacy and toxicity profiles of peptide-guided cytotoxic drugs relative to the parental free drugs were observed in tumor-bearing mice. We now hypothesize that the genetic progression of malignant tumor cells is paralleled by epigenetic changes within non-malignant cells in tumor blood vessels. Here we propose to study the molecular heterogeneity of angiogenic vasculature during tumor progression. Based on these studies, we will test whether there are stage-specific efficacy differences among anti-angiogenic drugs. In this proposal, we will evaluate the expression of antigenic markers in tumor vasculature and in human tumor samples using phage and antibodies that recognize antigenic markers. We will determine whether the expression of distinct sets of markers (i) correlates with differential responses to therapy and (ii) serves as a prognostic factor. We will evaluate selective induction of endothelial cell apoptosis by proapoptotic peptides targeted to antigenic markers in tumor vasculature. We will also determine whether targeting of distinct sets of markers in tumor blood vessels increases the therapeutic index of such therapies; to establish organ- and tumor-homing peptides as tools for vascular imaging in vivo using selective circulating probes isolated by in vivo phage display and to select peptides that bind to endostatin in vitro and isolate endostatin receptor(s). We will correlate the outcome of endostatin treatment with the expression of the candidate endostatin receptor(s).

说明：（申请人提供） 我们开发了一种体内选择系统，其中噬菌体能够 从噬菌体展示中恢复对不同组织的选择性归巢 静脉内给药后的肽库。使用这个策略，我们 已经分离出几种定位正常器官或肿瘤的肽。我们有 研究表明，这些肽中的每一个都与不同的受体结合 选择性表达于靶组织的脉管系统上。肿瘤归巢 肽靶向在肿瘤血管生成中上调的受体 脉管系统。功效和毒性特征显着改善 相对于亲本游离药物，肽引导的细胞毒性药物是 在荷瘤小鼠中观察到。我们现在假设遗传 恶性肿瘤细胞的进展与表观遗传变化并行 肿瘤血管中的非恶性细胞内。在这里我们建议学习 肿瘤过程中血管生成脉管系统的分子异质性 进展。基于这些研究，我们将测试是否存在阶段特定的 抗血管生成药物之间的疗效差异。在这个提案中， 我们将评估肿瘤血管系统中抗原标记的表达， 使用识别抗原的噬菌体和抗体在人类肿瘤样本中 标记。我们将确定不同标记组的表达是否 (i) 与治疗的不同反应相关，并且 (ii) 作为 预后因素。我们将评估内皮细胞的选择性诱导 靶向肿瘤抗原标记的促凋亡肽促进细胞凋亡 脉管系统。我们还将确定是否针对不同的组 肿瘤血管中的标记物增加了此类疾病的治疗指数 疗法；建立器官和肿瘤归巢肽作为血管的工具 使用体内噬菌体分离的选择性循环探针进行体内成像 展示并选择体外与内皮抑素结合的肽并分离 内皮抑素受体。我们将关联内皮抑素治疗的结果 与候选内皮抑素受体的表达。