Although radiation therapy is a mainstay of cancer management, significant numbers of radiotherapy patients treated with curative intent still ultimately fail. Traditional methods of improving cancer therapy have focused primarily on achieving increased tumor cell kill. However, over the last decade another treatment approach has emerged. This strategy aims to impair the tumor's nutritional support system by target the tumor blood vessel network. Such "Vascular Targeting" approaches are based on the recognition that a continuously expanding vasculature is an essential requirement for tumor initiation, progression and metastasis. Vascular Disrupting Agents (VDAs) are designed to cause a rapid and selective vascular shutdown in tumors. The resulting ischemia produces rapid and extensive tumor cell kill. A main focus has been on agents that reversibly bind with tubulin and prevent microtubule assembly. Treatment with such VDAs has been shown to lead to extensive tumor necrosis in a wide variety of tumor models and to synergistic interactions with conventional anticancer treatments including radiotherapy. The latter has been attributed to the ability of these agents to selectively destroy central regions of tumors, areas widely believed to contain cell populations resistant to cytotoxic therapies. Lead VDAs have now entered clinical trials but new questions regarding their successful application have arisen. One of the issues to be addressed in this research program is whether the steps considered to ameliorate VDA-treatment associated hypertension might actually compromise the antitumor efficacy of these agents. Secondly we will examine whether knowledge of pathophysiologic information obtained using doses closer to those attainable in the clinic will allow the optimization of dose scheduling and drug delivery, leading to superior antitumor efficacy. The final aspect of this research proposal will explore the potential of utilizing the quantification of VDA treatment induced mobilization of circulating endothelial progenitor cells as potential biomarkers of VDA activity. Studies will be carried out with the current lead tubulin binding VDA CA4P and its promising second generation analog OXi4503 which has also entered patient trials. We believe that the proposed preclinical investigations will yield critical insights to the questions posed and provide valuable guidelines/suggestions for future clinical VDA initiatives in oncology.

Public Health Relevance

The central goal of these studies is to examine the potential of applying vascular targeting strategies to improve cancer therapy. Experiments are designed to investigate how to deliver such therapies for maximum antitumor efficacy as well as determining the potential of developing predictive indicators of their treatment response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA084408-12
Application #
8204588
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Bernhard, Eric J
Project Start
2000-01-24
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
12
Fiscal Year
2012
Total Cost
$312,263
Indirect Cost
$99,114
Name
University of Florida
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Magdoom, Kulam Najmudeen; Pishko, Gregory L; Rice, Lori et al. (2014) MRI-based computational model of heterogeneous tracer transport following local infusion into a mouse hind limb tumor. PLoS One 9:e89594
Biel, Nikolett M; Siemann, Dietmar W (2014) Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference. Cancer Lett :
Siemann, Dietmar W (2011) The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by Tumor-Vascular Disrupting Agents. Cancer Treat Rev 37:63-74
Bertelsen, Lotte B; Shen, Yuan Yuan; Nielsen, Thomas et al. (2011) Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation. Int J Radiat Biol 87:1126-34
Rice, Lori; Pampo, Christine; Lepler, Sharon et al. (2011) Support of a free radical mechanism for enhanced antitumor efficacy of the microtubule disruptor OXi4503. Microvasc Res 81:44-51
Madlambayan, Gerard J; Meacham, Amy M; Hosaka, Koji et al. (2010) Leukemia regression by vascular disruption and antiangiogenic therapy. Blood 116:1539-47
Wankhede, Mamta; Dedeugd, Casey; Siemann, Dietmar W et al. (2010) In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503. Oncol Rep 23:685-92
Baguley, Bruce C; Siemann, Dietmar W (2010) Temporal aspects of the action of ASA404 (vadimezan; DMXAA). Expert Opin Investig Drugs 19:1413-25
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
Siemann, Dietmar W; Horsman, Michael R (2009) Vascular targeted therapies in oncology. Cell Tissue Res 335:241-8

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