VIRGINIA COMMONWEALTH UNIVERSITY
Grant: $270,775 - National Institutes of Health - Sep. 15, 2009
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Award Description: Targeting tumor vessels has become an important approach for cancer therapy. In addition to widely used anti-angiogenic agents, vascular disrupting agents have moved into clinical studies but face a major problem in cardiotoxicity. A new vascular disrupting agent, cis-3, 4, 5-trimethoxy-3-aminostilbene (stilbene 5c), has been developed. Various imaging modalities have confirmed that stilbene 5c inhibits tumor growth and suppresses tumor blood flow to induce hypoxia in mouse xenografts. In contrast to the existing vascular disrupting agents, stilbene 5c has negligible cardiotoxicity verified by histology and echocardiogram analysis of stilbene-treated mice. A synergistic effect between stilbene 5c and anti-angiogenic agent bevacizumab provides a new strategy to further enhance the therapeutic efficacy of stilbene 5c. We hypothesize that tumor treated with stilbene 5c will develop pathophysiologic responses secondary to stilbene-induced tumor ischemia and hypoxia. The alteration of tumor blood flow after stilbene treatment and the mechanism of tumor responses will be investigated so that rational combination can be developed to optimize its clinic application. Aim 1 will confirm that stilbene 5c suppresses tumor growth by blocking tumor blood flow. The longitudinal changes of tumor blood flow will be examined to determine the optimal schedule for repetitive dosing. Aim 2 will investigate the role of clotting cascade and platelet activation in tumor blood flow suppression after administration of stilbene. Nitric oxide-induced vasodilatation will be investigated for inducing rebound recovery of tumor blood flow. The level of nitric oxide synthase and the downstream markers of nitric oxide will be analyzed in tumor specimens treated with stilbene. Nitric oxide synthase inhibitor will be combined with stilbene 5c to determine if the combination enhances the therapeutic efficacy of stilbene 5c. Aim 3 will investigate the role of HIF-1?-induced production of VEGF or other cytokines in hypoxic tumor. Potential candidates of cytokines induced by stilbene 5c will be identified by an angiogenesis array and siRNA will be used to down-regulate HIF-1?, VEGF, SDF-1 or the identified cytokines. The mobilization of bone marrow derived progenitor cells will be analyzed in mice with tumor xenografts derived from siRNA-expressing tumor cells. The therapeutic efficacy of stilbene will be tested after blocking VEGF or SDF-1. Finally, combination with conventional chemotherapeutic agent cisplatin will be evaluated for synergism. Successful completion of this proposal will facilitate the clinical application of stilbene 5c as a useful vascular disrupting agent.
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