Glioblastoma (GM) is the most common type of glioma and is considered incurable. Despite recent advances in the combined use of post-surgical chemotherapy and radiation only 26% of patients remain alive at 2 years. Therefore, new treatment strategies are desperately needed for this patient population. One of the pathological hallmarks of GM is endothelial proliferation. Angiogenesis of GM is driven by VEGF via the endothelial receptor, VEGFR2. VEGFR2 is the major mediator of several physiological and pathological effects of VEGF-A on endothelial cells, including proliferation and survival, migration and permeability. AZD2171 is a potent inhibitor of VEGFR2 and in rodent models containing colorectal cancer xenografts has been shown to reduce both vascular permeability and vascular volume. Preclinical studies have demonstrated that interruption of VEGF signaling pathways inhibits glioma growth and reduces vascular permeability of the tumor. We have proposed a phase 2 study of AZD2171 in patients with recurrent GM. In this study the primary objective is the percentage of patients alive and progression free 6 months after the start of therapy, a commonly used endpoint in this patient population. In order to assess the potential anti-angiogenic effects of AZD2171 we are also proposing to measure the number of circulating endothelial cells as well as a number of circulating angiogenic proteins including VEGF. In previous studies of other anti-angiogenesis therapies it has been shown that some of these parameters are reduced once treatment is started and may serve as a relatively non-invasive method of determining the biological effect of anti-angiogenesis therapies. Finally, we also propose the utilization of serial non-invasive magnetic resonance imaging (MRI) to measure the potential vascular effects of AZD2171 on the tumor. MRI techniques that will be utilized include dynamic contrast enhanced imaging, arterial spin labeling and perfusion weighted imaging in an effort to detect changes in tumor perfusion, permeability and blood flow. The laboratory and imaging parameters will be obtained prior to AZD2171 therapy and at serial time points after the initiation of treatment with this drug. Incorporation of these correlative techniques into this phase 2 study represent unique strengths of our institution and will enhance our ability to assess the potential efficacy of AZD2171 in a multidimensional manner. ? ?
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