THE CHILDRENS HOSPITAL LOS ANGELES
The scientific purpose of this adminitrative supplement is to increase the pace of scientific discovery for our currently funded parent grantby advancing biomaker analysis and targeted tumor treatment strategies associated with Photodynamic Therapy (PDT). Our laboratory was the first to discover and report that PDTmediated tumor tissue injury coudl induce expression of pro-angiogenic/pro-survival molecules (VEGF, HIF- 1a, SDF-1a, COX-2,MMPs,AKT, survivin) within the tumor microenvironment and that clinically releventinhibitors targeted to these molecules could imrpove PDT responsiveness. The overall goals of our currentlyfunded parent grant are to understand the mechanisms of how PDT modules the tumormicroenvironment/vasculature and to translate this knowledge to expand novel targeted and combined-modality treatment approaches. It has been reported that circulating endothelial progenitor cells (CEPs) are elevated in reponse to vascular injury and that factors such as VEGF and SDF-1a (which we have discovered are induced by PDT) cause increased homing of CEPs to tumor neo-vasculature. We have recently obtained new preliminary data showing that PDT can modulate CEC and CEP levels in preipheral blood and that PDT does induce expression of SDF-1a in treated tumor tissue. The gaol of or administrative supplement is to accelerate and advance our current research approach by specifically examing the role of CECs and CEPs as relevant biomarkers of PDT induced vascular injury and treatment respone. We will also determine if targeting CEPS can improve PDT efficacy. The specific aims of our administrative supplement are: 1) to determine the levels of CECs and CEPs following PDT in a murine mammary carcinoma tumor model and correlate these markers wwith treatment response, and 2) to determine if blocking CEP mobilization and incorporation into tumor neovasculature can improve PDT by blocking angiogenesis and vasculogenesis. The proposed work in our administrative supplement is a direct extension of our current parent grant and the data obtained will significantly enhance the knowledge base resulting from our parent grant.