Our overall goal is to improve the cure rates of glioblastoma multiforme (GBM) for which treatment failure leading to patient death is the result of inability to control the primary tumor by radiotherapy. To do this we plan to exploit the hypothesis that the failure to cure these tumors despite high dose radiotherapy is the result of regrowth of the tumor vasculature from circulating cells (a process known as vasculogenesis) following the course of radiotherapy. Targeting both the local tumor and vasculogenesis, primarily mediated by CD11b+ myelomonocytes and circulating endothelial cells (ECs), is a novel paradigm and could lead to a major increase in the curability of tumors by radiotherapy. We will test three drugs that inhibit vasculogenesis pathway, in two GBM model systems: 1) AMD3100, a specific inhibitor of the interaction of stromal derived factor-1 (SDF-1) with its receptor CXCR4. This interaction is responsible for the retention of the CD11b+ myelomonocytes in tumors after irradiation, 2) CCX662, a specific inhibitor of the interaction of SDF-1 with its second receptor, CXCR7, which we believe is responsible for the recruitment of circulating ECs and their capture in the irradiated tumor, and 3) NOX-A12, a highly specific inhibitor of SDF-1 which we hypothesize will prevent both the CD11b+ monocytes and circulating ECs from colonizing the irradiated tumor. The two GBM models systems we will use are the intracranially implanted human U251 GBM in the mouse and the ENU-induced GBM in the rat. We will test all three drugs given for 3-4 weeks, and for longer, following either single or fractionated irradiation to each of these tumors models and will determine their efficacy in preventing the radiation increased influx of CD11b+ and ECs and on for their ability to prevent recurrences of the tumors following the modest radiation doses that we will use. We will also test in the mouse model the ability of our strategy to work with focal tumor irradiation rather than whole brain irradiation. Our project combines the expertise of three laboratories, that of Dr. Brown, an experimental investigator with expertise in tumor radiation biology, that of Dr. Recht, a neurooncologist who treats GBM patients and whose laboratory has expertise with initiation and detection of the ENU-induced rat GBM model and Dr. Graves who built the micro-CT based irradiator. The goal is to provide the needed information to allow clinical testing of this new strategy. )
Our goal is to improve the cure rates of glioblastoma multiforme (GBM), a devastating brain cancer. Radiotherapy is a key part of the treatment of GBM, but despite the high doses of radiation that are given the tumors invariably recur within the radiation field. We have shown that we can prevent, or markedly delay, the recurrence of experimental GBM in mice and rats by preventing the accumulation within the irradiated tumors of circulating cells that can form blood vessels. This application proposes using three drugs that inhibit these circulating cells to determine their optimum use for subsequent clinical studies.
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