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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Bernhard, Eric J
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University of Florida
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Biel, Nikolett M; Siemann, Dietmar W (2016) Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference. Cancer Lett 380:525-33
Scharf, Valery F; Farese, James P; Coomer, Alastair R et al. (2013) Effect of bevacizumab on angiogenesis and growth of canine osteosarcoma cells xenografted in athymic mice. Am J Vet Res 74:771-8
Molnar, Nikolett; Siemann, Dietmar W (2012) Inhibition of endothelial/smooth muscle cell contact loss by the investigational angiopoietin-2 antibody MEDI3617. Microvasc Res 83:290-7
Siemann, Dietmar W; Dong, Meiyu; Pampo, Chris et al. (2012) Src-signaling interference impairs the dissemination of blood-borne tumor cells. Cell Tissue Res 349:541-50
Tang, Ming; Chen, Bo; Lin, Tong et al. (2011) Restraint of angiogenesis by zinc finger transcription factor CTCF-dependent chromatin insulation. Proc Natl Acad Sci U S A 108:15231-6
Dai, Yao; Bae, Kyungmi; Siemann, Dietmar W (2011) Impact of hypoxia on the metastatic potential of human prostate cancer cells. Int J Radiat Oncol Biol Phys 81:521-8
Madlambayan, Gerard J; Meacham, Amy M; Hosaka, Koji et al. (2010) Leukemia regression by vascular disruption and antiangiogenic therapy. Blood 116:1539-47
Siemann, Dietmar W; Horsman, Michael R (2009) Vascular targeted therapies in oncology. Cell Tissue Res 335:241-8
Siemann, Dietmar W; Brazelle, W D; J├╝rgensmeier, Juliane M (2009) The vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor cediranib (Recentin; AZD2171) inhibits endothelial cell function and growth of human renal tumor xenografts. Int J Radiat Oncol Biol Phys 73:897-903
Siemann, Dietmar W; Norris, Christina M; Ryan, Anderson et al. (2009) Impact of tumor cell VEGF expression on the in vivo efficacy of vandetanib (ZACTIMA; ZD6474). Anticancer Res 29:1987-92

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