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.
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