Radiation therapy is one of the mainstays of cancer management. Indeed common clinical practice integrates this therapeutic modality with surgery and chemotherapy into definitive treatment strategies of advanced cancers. Yet despite intensive application of combined modality therapies, significant numbers of radiotherapy patients treated with curative intent ultimately fail. While reasons for radiotherapy failures vary, abnormal tumor microenvironments, tumor progression, and metastatic spread of neoplastic cells are believed to be major contributors. Since these resistance factors are affected by a tumor's ability to develop and maintain a functional blood vessel network, the application of novel vascular targeting approaches in a radiotherapy setting is likely to improve treatment outcomes. Indeed combining strategies that inhibit tumor angiogenesis with radiotherapy can amplify the antitumor effects of radiation. Still, many questions regarding the successful application of this new approach to cancer treatment remain. The central goal of the present application is to develop new insights into the underlying mechanisms of angiosuppressive therapy and to explore avenues to maximize its therapeutic potential. One of the issues to be addressed in this research program is whether the extent of a tumor's inherent vascularity predicates its response to antiangiogenic therapies, i.e. will highly vascular tumors be most susceptible to such interventions? Secondly four color flow cytometric analysis and a green fluorescent protein (GFP) bone marrow transplant model will utilized to investigate the role of circulating endothelial progenitor (CEP) cells in tumor angiogenesis and response to angiosuppressive therapy. Treatments to be examined include those directed at specific aspects of the vascular endothelial growth factor (VEGF) signaling cascade (ligand and VEGF tyrosine kinase inhibition) as well as modulation of the endogenous inhibitor of angiogenesis, endostatin. The former will examine small molecule targeting strategies while the latter will utilize a self-complimentary recombinant adeno associated virus (SC AAV) transduction of skeletal muscle as a platform for angio-suppressive protein delivery. Finally the hypothesis that simultaneously interfering with multiple aspects of angiogenesis will lead to superior responses in tumors will be explored by combining therapies targeting different points in the same signaling pathway or different components of the angiogenic process in general. The ability of the most efficacious vessel targeting strategy will then be tested in a fractionated radiotherapy setting to test its potential to improve treatment outcomes. The central goal of these studies is to examine the potential of applying vascular targeting strategies to enhance the response of solid tumors to radiation therapy. Experiments are designed to investigate the mechanisms underlying the interaction between such therapies and to develop approaches that would maximize the anti-tumor efficacy of such combined treatments. ? ? ?
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