Targeted Assessment of Antiangiogenic Therapy

抗血管生成治疗的靶向评估

• 批准号: 6489442
• 负责人: JAMES L. ABBRUZZESE
• 金额: $ 194.87万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-16 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6489442
• 关键词: angiogenesis; angiogenesis inhibitors; cooperative study; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy

Validated markers of biologic activity for anti-angiogenic agents are not available and the assessment of clinically relevant and reproducible activity for these drugs is likely to be complex. Therefore, this application seeks to develop methods that will allow the diverse biologic processes contributing to angiogenesis to be assessed in patients. The long-term objective of this proposal will be to: develop reproducible methods to evaluate the molecular and cellular events that mediate anti-angiogenic effects in tumors and to use these methods to directly (analysis of tumor tissue) and indirectly (non-invasive imaging) evaluate anti-angiogenic treatment strategies in the clinic. Our primary focus will be to develop techniques to assess angiogenesis in patients using, 1. innovative immunohistochemical and biochemical tests developed in our laboratories and, 2. non-invasive imaging. To validate that these techniques can be applied to the clinical development of anti-angiogenic therapies, we will assess candidate biochemical assays and non-invasive techniques through the ongoing and proposed pre-clinical studies and clinical trials outlined in this proposal. We hypothesize that there are interim measures of anti-angiogenic activity that will enable early, accurate clinical assessment of anti-angiogenic therapies. To accomplish our long-term objective we propose a program of integrated Research Projects, Developmental Programs and Core Units with the following specific goals: (1) To clinically validate the relevance of putative surrogate markers of angiogenesis/anti-angiogenesis and the specific signaling pathways through which they control the expression of angiogenic proteins; (2) To clinically validate specific methods, developed in preclinical models, for detecting endothelial cell apoptosis in response by anti-angiogenic therapies; (3) To develop techniques to assess the molecular heterogeneity of tumor blood vessels, thereby improving our understanding of the biologic basis for responsiveness or resistance to anti-angiogenic therapies, and to use this information to develop noel targeted imaging strategies; (4) To develop and clinically validate non-invasive methods to assess the effectiveness of anti- angiogenic agents.

抗血管生成剂的生物活性的经过验证的标志物尚不可用，并且对这些药物的临床相关性和可重复性活性的评估可能很复杂。因此，本申请旨在开发能够在患者中评估有助于血管生成的多种生物过程的方法。该提案的长期目标是：开发可重复的方法来评估介导肿瘤中抗血管生成作用的分子和细胞事件，并使用这些方法直接（肿瘤组织分析）和间接（非侵入性成像）评估临床中的抗血管生成治疗策略。我们的主要重点是开发技术来评估患者的血管生成，使用 1. 我们实验室开发的创新免疫组织化学和生化测试，以及 2. 非侵入性成像。为了验证这些技术可以应用于抗血管生成疗法的临床开发，我们将通过本提案中概述的正在进行的和拟议的临床前研究和临床试验来评估候选生化测定和非侵入性技术。我们假设存在抗血管生成活性的临时措施，这将使抗血管生成疗法的早期、准确的临床评估成为可能。 为了实现我们的长期目标，我们提出了一个由综合研究项目、发展计划和核心单元组成的计划，其具体目标如下：（1）临床验证血管生成/抗血管生成的假定替代标记物的相关性以及它们控制血管生成蛋白表达的特定信号传导途径； (2) 临床验证在临床前模型中开发的用于检测抗血管生成治疗反应中内皮细胞凋亡的特定方法； (3) 开发评估肿瘤血管分子异质性的技术，从而提高我们对抗血管生成治疗的反应性或耐药性的生物学基础的理解，并利用这些信息开发 noel 靶向成像策略； (4) 开发并临床验证非侵入性方法来评估抗血管生成药物的有效性。