Project Funding Details

Brain cancer remains amongst the most lethal type of malignancy, highly resistant to conventional therapies. Although anti-angiogenic approaches hold promise, clinical experience with VEGF inhibitors has proven disappointing. Perhaps, VEGF was the wrong target? Detailed examination of Wnt signaling in the embryonic central nervous system shows that this pathway is specifically required for CNS angiogenesis. The Rowitch laboratory at UCSF has recently shown that oligodendrocytes maintain a Wnt-activated program of angiogenesis at postnatal stages (Yuen et al., 2014, Cell in press). Moreover, many laboratories have shown conservation of oligodendrocyte-like features in human glioma. Therefore, we will test the hypothesis that gliomas have co-opted a mechanism for angiogenesis that is normally required during CNS development, and in particular that human pediatric gliomas rely on Wnt-driven angiogenesis for neovascularization. The major significance of this study is that we may identify a novel pathway to target for angiogenic therapy. The Wnt pathway is specifically required for CNS angiogenesis but not maintenance of CNS vasculature. Therefore, Wnt inhibitor therapy should have specificity for neovascularization without danger of causing hemorrhage in intact brain tissue. Although Wnt inhibitors carry systemic side effects, some of these are undergoing phase I studies and, moreover, delivery in brain cancer can be done through convection-enhanced delivery (local) bypassing systemic side effects.