High-grade gliomas are the leading cause of brain tumor-related death, underscoring the urgent need for a deeper understanding of high-grade glioma pathobiology and novel avenues for therapy. We have recently discovered that neuronal activity robustly promotes high-grade glioma growth and that a synaptic molecule called neuroligin-3 is a crucial activity-regulated mechanism for glioma growth. Activity-regulated cleavage and release of neuroligin-3 from synapses, mediated by the protease ADAM10, is required for glioma growth, although it is not yet clear what mediates this striking dependency. Further, we have found that a subset of xenografted gliomas evolve in vivo to circumvent neuroligin-3 dependency over a period of 6 months in the context of a neuroligin-3 deficient brain microenvironment. In the present proposal, we seek to leverage single cell genomics together with patient-derived glioblastoma orthotopic xenografts and immunocompetent murine glioblastoma allografts in neuroligin-3 knockout or wild type mice to dissect neuroligin-3 signaling within the intact glioma ecosystem. Using a similar strategy, we will also uncover the mechanisms by which some xenografted gliomas circumvent neuroligin-3 dependency, findings that will inform not only neuron-glioma interactions but also fundamental mechanisms of glioma progression. Finally, we will perform preclinical efficacy and safety testing of ADAM10 inhibition to block neuroligin-3 release into the tumor microenvironment in an effort to provide sufficient preclinical evidence to bring this novel therapeutic strategy to a clinical trial for adult high-grade gliomas. This future trial will complement our Pediatric Brain Tumor Consortium-sponsored phase 1 clinical trial of ADAM10 inhibition for pediatric high grade glioma. Taken together, the proposed experiments will elucidate fundamental mechanisms of glioma growth and progression and advance a promising new therapeutic approach for these lethal brain cancers.
High-grade gliomas are the leading cause of brain tumor-related death. We have recently discovered that the activity of neurons in the tumor microenvironment promotes the growth of high-grade glioma through secretion of a synaptic protein called neuroligin-3. Neuroligin-3 not only acts as a potent mitogen in vitro, but is also strictly necessary for glioma growth in vivo. The present proposal seeks to understand why high-grade gliomas exhibit such a strong dependency on this molecule and how some tumors evolve to find a way to circumvent this dependency. Finally, we will test a new therapeutic strategy to block neuroligin-3 in the tumor microenvironment. The results of these experiments will deepen our understanding of these deadly cancers and may also advance a new therapy to treat high-grade gliomas.
Showing the most recent 10 out of 84 publications
