Anti-VEGF antibody therapy with bevacizumab provides significant clinical benefit and is increasingly becoming the standard of care for patients with recurrent glioblastoma multiforme (GBM). Unfortunately, progression on bevacizumab therapy in a subset of patients is associated with an aggressive, diffuse, multi- focal disease recurrence pattern and a short subsequent survival interval. Using a novel primary human GBM xenograft model, we have reproduced a similar phenotype in which bevacizumab therapy results in increased glioma invasiveness and in a multi-focal disease recurrence pattern. Our preliminary data also suggest that glioma invasion is critically controlled by Src- and PI3-kinase-depedent signaling pathways. Based on these data, we hypothesize that the increased invasiveness associated with anti-VEGF therapy is due to increased signaling through these pathways. Consistent with this hypothesis, we found that the Src-family kinase (SFK) inhibitor dasatinib can prevent both the increased invasion and the multi-focal disease progression pattern induced by bevacizumab. In part based on these preliminary data, we are initiating a clinical trial testing the combination of bevacizumab and dasatinib in patients with recurrent GBM. The focus of this application is to rigorously examine the influence of SFK and PI3K signaling on the pro-invasive effects of bevacizumab both in primary GBM orthotopic xenograft models and in patients with recurrent GBM.
The specific aims are: 1. Assess the combined effects of bevacizumab and dasatinib on GBM invasion. 2. Examine the role of individual SFKs and specific downstream signaling effectors on bevacizumab-induced invasion. 3. Examine the combined effect of SFK and PI3K inhibition on GBM migration and invasiveness, and test the effects of dual inhibition on bevacizumab responsiveness.
Anti-VEGF therapy is associated with significant prolongation in progression-free survival in patients with recurrent GBM, although ultimate disease progression on this therapy is associated with aggressive disease and a short subsequent survival interval. The focus of this application is to understand whether molecularly-targeted therapies can prevent the pro-invasive effects of anti-VEGF therapy. Ultimately this strategy may provide additional survival benefit for patients with this deadly disease.
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