The aberrant vascular morphology, spatial heterogeneity in vessels, and metabolic microenvironments associated with solid tumors, are major factors contributing to treatment failures in radiotherapy. Since all of these may be affected by treatment with vascular targeting agents (VTAs), the combination of such agents with radiotherapy is likely to improve treatment outcomes. Indeed, we previously have shown that combining a VTA with radiotherapy would allow the two treatments to act in a complimentary fashion in tumors at the microregional level resulting in an overall amplification of the antitumor effects of radiation. Though clearly promising, 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 vascular targeting therapy and to explore new avenues to maximize its therapeutic potential. One of the issues to be addressed in this research program is whether at lower doses than have typically be used pre-clinically, but closer to those attainable in the clinic, enhancement of radiation response by VTAs is still feasible. Secondly, we propose to examine whether post VTA treatment conditions provide a favorable setting for the application of antiangiogenic therapies. This strategy is based on the observation that cells surviving VTA treatment at the tumor periphery aggressively promote neovascularization in order to achieve the rapid regrowth that occurs from the viable rim. A third component of the program is focused on the evaluation of new emerging second generation compounds as current VTAs progress through early clinical trial evaluations. Specifically the antitumor potency and potential superiority of a recently identified lead candidate analog of combretastatin will be examined. Finally, based on the hypothesis that targeting the tumor neovasculature should offer the possibility of inducing responses in all tumors with an established vessel network, we will examine whether in addition to their activity in primary tumors, VTAs can impact the management of metastatic disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA084408-08
Application #
7211346
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
2004-04-01
Project End
2008-09-30
Budget Start
2007-04-01
Budget End
2008-09-30
Support Year
8
Fiscal Year
2007
Total Cost
$281,312
Indirect Cost
Name
University of Florida
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
969663814
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
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
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
Siemann, Dietmar W; Chaplin, David J; Walicke, Patricia A (2009) A review and update of the current status of the vasculature-disabling agent combretastatin-A4 phosphate (CA4P). Expert Opin Investig Drugs 18:189-97
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

Showing the most recent 10 out of 32 publications