Photodynamic therapy (PDT) continues to be an effective clinical procedure for treating solid tumors but the procedure has not been optimized and recurrences can occur. The long-term objective of our proposal is to improve upon the efficacy of PDT. The rationale for this application builds upon observations that PDT induces significant changes within the tumor microenvironment that can lead to an angiogenic and/or survival phenotype. We have found that PDT can induce expression of vascular endothelial growth factor (VEGF) within treated tumors. Additional angiogenic factors, including matrix metalloproteinase-9 (MMP-9) as well as survival molecules, Akt and survivin, are increased and/or activated following PDT. We hypothesize that combining PDT with appropriately targeted and delivered angiogenic inhibitors will significantly improve the long-term therapeutic responsiveness of PDT. We further hypothesize that PDT mediated changes within the tumor microenvironment associated with the expression and activation of MMP- 9 and survivin can decrease PDT efficacy.
Three specific aims will address our hypotheses.
In specific aim 1 we will determine how best to combine antiangiogenic therapy to optimize PDT efficacy. Antiangiogenic agents that target VEGF (Avastin), VEGF receptor-2 (DC 101),and the receptor tyrosine kinase of VEGF (ZD6474) will be evaluated in experiments designed to examine tumor and normal tissue response.
In specific aim 2, we will determine the impact that PDT induced alterations to the tumor microenvironment associated with MMP-9 expression and activation have on modulating treatment responsiveness. MMP-9 knockout mice will be used to determine the role of this proteinase in PDT outcomes.
In specific aim 3, we will determine the impact of survivin expression and activation within the tumor microenvironment on PDT responsiveness. Tumors genetically modified to express wild type or a dominant negative mutant form of survivin will be used to determine the role of this inhibitor of apoptosis in modulating PDT tumor response. We will also determine the effectiveness of combining PDT with the Hsp90/survivin inhibitor 17-AAG[17- (allylamino)-17-demethoxygeldanamycin). The successful completion of these aims will provide mechanistic information regarding PDT modulation of the tumor microenvironment and translational data needed to justify including targeted inhibitors with PDT.
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