A pathophysiological hallmark of glioblastoma (GBM) is the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic cytokines, which, in turn, stimulate endothelial cell proliferation, migration and survival. The result is a highly abnormal tumor vascular network that promotes tumor growth and may impair the efficacy of cytotoxic therapies by enhancing tumor hypoxia and impairing drug delivery. The mechanism of action of anti-VEGF therapies is incompletely understood. The "classical" view is that anti-VEGF therapy decreases tumor vessel perfusion and "starves" the tumor of oxygen and essential nutrients. In contrast, the vascular normalization hypothesis holds that anti-VEGF therapy enhances chemo radiation by transiently normalizing tumor blood vessels, reducing hypoxia and improving chemotherapy delivery. Based on our preclinical and clinical studies of different anti-VEGF therapeutics across multiple solid tumor subtypes, including GBM, we hypothesize that anti-VEGF therapies achieve clinical benefit by transiently normalizing tumor blood vessels. Bevacizumab, a humanized, monoclonal antibody against the VEGF-A ligand, was approved as monotherapy for recurrent GBM (rGBM) in 2009. However, responses to bevacizumab are variable, most responses are not durable and the mechanism of action in GBM is not established. To date, no reliable imaging or biospecimen markers of tumor response versus resistance to bevacizumab exist and this expensive and potentially toxic therapy is administered to all rGBM patients. Based on our preclinical studies using orthotopic GBM models and our findings in newly diagnosed GBM (nGBM) and rGBM patients treated with the pan-VEGF receptor tyrosine kinase inhibitor, cediranib, we advance the following hypotheses: 1) Bevacizumab achieves maximal therapeutic benefit in a subset of GBM patients by transient normalization of tumor vessels leading to alleviation of brain edema, reduction in tumor hypoxia and enhanced delivery of temozolomide;2) Imaging and biospecimen markers of vascular normalization are useful in the identification of responsive versus resistant GBM subpopulations;3) Bevacizumab resistance develops due to the activation of alternative pro-angiogenic or pro-invasive signal transduction pathways. In this competing renewal application, we build on our observations in GBM patients treated with cediranib and extend and expand these studies to patients treated with bevacizumab, the only approved anti-VEGF therapeutic for GBM. We will analyze biospecimen and imaging markers of response versus resistance in the rGBM patient population with an emphasis on vascular normalization and how the latter impacts the hypoxic tumor microenvironment, chemotherapy delivery and tumor cell proliferation.
Glioblastoma is a highly lethal form of brain cancer that is dependent on the formation of tumor blood vessels for growth and invasion. Although therapies that target these tumor blood vessels are being developed only some glioblastoma patients have lasting responses to these anti-angiogenic treatments. Building on promising data from our earlier studies, the primary goals of this project are to define non-invasive radiological and blood markers that identify the group of glioblastoma patients most likely to benefit from anti-angiogenic treatments.
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