Radiotherapy is the most important non-surgical treatment for cancer. Even so, large numbers of patients still fail at the local treatment site. New treatment strategies aimed at improving tumor response are therefore of high interest and the tumor vasculature, which is critical for the growth and survival of the neoplastic cell population, offers an attractive target. The goal of this grant proposal is to investigate approaches for optimally combining antiangiogenic strategies with localized radiation therapy in order to improve overall tumor response. Investigations are focused on interfering with two activators of angiogenesis (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF)) and amplification of an endogenous suppressor (endostatin). The approach will be the delivery and transfer of cDNA coding for antisense VEGF/bFGF or endostatin using adeno-associated virus (AAV) or cationic liposomes. Experiments are designed to first characterize and optimize the proposed antiangiogenic approaches in tumor cells, fibroblasts and endothelial cells in vitro. These studies will include the examination of the effect of angiosuppression strategies on the paracrine communication between the various cell types and the determination of whether direct interactions occur between such strategies and radiation treatment. The in vivo efficacy of antiangiogenic treatments used in conjunction with radiation therapy will then be evaluated in xenograft models of AIDS associated Kaposi's Sarcoma and clear cell renal cell carcinoma. These models were chosen because we believe that these neoplasms' typical manifestation of extensive vascularization, coupled with their lack of satisfactory responses to traditional therapeutic interventions, make them excellent candidates for new therapeutic strategies such as antiangiogenic approaches. Both tumor response and critical normal tissue toxicities will be assessed to determine whether a therapeutic benefit can be achieved when angiosuppressive treatments and radiation are combined. We believe that these studies will provide essential insights into the therapeutic utility of employing antiangiogenic treatment strategies as adjuvants to radiotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA089655-01A1
Application #
6399750
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$238,516
Indirect Cost
Name
University of Florida
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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; Brazelle, W D; Jürgensmeier, 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
Madlambayan, Gerard J; Butler, Jason M; Hosaka, Koji et al. (2009) Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger. Blood 114:4310-9

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