Tumor blood flow increases after x-irradiation. Similarly, the tumor vascular window model shows that tumor blood vessels are resistant to radiation as compared to blood vessels in more sensitive tumors. The applicant proposes that the signal transduction pathways required for endothelial survival and repair are targets to improve the therapeutic effects of ionizing radiation. The survival pathway activated by angiogenic ligands, such as VEGF and angiopoietein-1, mediate signal transduction through PI3 kinase and protein kinase B (Akt). Akt in turn, inhibits programmed cell death (apoptosis) by increased expression of Bcl-2 and Bcl-XL and through phosphorylation of Bad. His preliminary data show that inhibition of Flk-1 or PI3 kinase blocks the survival pathway and allows for radiation-induced apoptosis. He has focused on the VEGF R2 (Flk-1) receptor tyrosine kinase by use of specific inhibitors of Flk-1 (soluble Flk-1 and SU5416). Flk-1 inhibition enhanced radiation-induced apoptosis and HUVEC and 3B11 endothelial cells. Likewise, inhibitors of PI3 kinase block the survival pathway and enhance radiation-induced apoptosis in endothelial cells. To determine whether Flk-1 inhibition enhances the radiation effect in tumor vascular endothelium, he utilized the tumor vascular window and tumor blood flow analysis by Doppler ultrasound. The applicant's preliminary data show that both soluble Flk-1 and SU5416 block the resistance phenotype in vascular endothelium in blood vessels of all tumor types. Flk-1 also activates an endothelial repair pathway that consists of proliferation, migration and recruitment of endothelial progenitor cells. He, therefore, studied recruitment of endothelial progenitor cells into irradiated tumors. This showed that Flk-1+ endothelial progenitors extravasate from the tumor microvasculature into the perivascular space of irradiated tumors. He hypothesizes that the Flk-1 receptor is required for this repair process and that Flk-1 inhibition will improve radiation responsiveness in tumors. In the proposed studies, the applicant will determine the mechanisms of Flk-1-mediated survival in irradiated tumor blood vessels. He will study signal transduction through PI3 kinase and Akt. He will also determine whether this signal transduction pathway inhibits radiation-induced apoptosis by increased expression of Bcl-2 of Bcl-XL and phosphorylation of Bad. He will determine whether the Flk-1 receptor is required for repair of the tumor microvascular endothelium. Each of these findings will be applied to Specific Aim 4, in which he will optimize the administration of Flk-1 inhibitors to improve the tumor control by ionizing radiation.
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