Targeted Assessment of Antiangiogenic Therapy

抗血管生成药物的生物活性的验证标志物不可用，这些药物的临床相关性和可重复活性的评估可能很复杂。因此，本申请寻求开发允许在患者中评估有助于血管生成的不同生物过程的方法。本提案的长期目标是：开发可重复的方法来评价介导肿瘤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）评价临床抗血管生成治疗策略。我们的主要重点将是开发技术，以评估血管生成的患者使用，1。创新的免疫组织化学和生化测试在我们的实验室开发，2。非侵入性成像为了验证这些技术可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评估候选生化测定和非侵入性技术。我们假设有抗血管生成活性的临时措施，这将使早期，准确的临床评估抗血管生成治疗。 为了实现我们的长期目标，我们提出了一个综合研究项目，开发项目和核心单元的计划，具体目标如下：（1）临床验证推定的血管生成/抗血管生成的替代标志物的相关性及其控制血管生成蛋白表达的特定信号通路;（2）临床验证在临床前模型中开发的用于检测抗血管生成疗法响应的内皮细胞凋亡的特定方法;（3）发展肿瘤血管分子异质性评价技术，从而提高我们对抗血管生成疗法的反应性或抗性的生物学基础的理解，并利用这些信息开发诺埃尔靶向成像策略;（4）开发和临床验证非侵入性方法来评估抗血管生成剂的有效性。

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.