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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Hubbard, Leah
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
McBrayer, Samuel K; Mayers, Jared R; DiNatale, Gabriel J et al. (2018) Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell 175:101-116.e25
McKenney, Anna Sophia; Lau, Allison N; Somasundara, Amritha Varshini Hanasoge et al. (2018) JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J Clin Invest 128:789-804
Shankar, Ganesh M; Kirtane, Ameya R; Miller, Julie J et al. (2018) Genotype-targeted local therapy of glioma. Proc Natl Acad Sci U S A 115:E8388-E8394
Arvanitis, Costas D; Askoxylakis, Vasileios; Guo, Yutong et al. (2018) Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption. Proc Natl Acad Sci U S A 115:E8717-E8726
Li, Ben B; Qian, Changli; Roberts, Thomas M et al. (2018) Targeted Profiling of RNA Translation. Curr Protoc Mol Biol :e71
Nowosielski, Martha; Wen, Patrick Y (2018) Imaging Criteria in Neuro-oncology. Semin Neurol 38:24-31
Li, Ben B; Qian, Changli; Gameiro, Paulo A et al. (2018) Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins. Proc Natl Acad Sci U S A 115:E9325-E9332
Khandekar, Melin J; Jain, Rakesh (2018) Smooth sailing for immunotherapy for unresectable stage III non-small cell lung cancer: the PACIFIC study. Transl Cancer Res 7:S16-S20
Zhang, Na; Chen, Jie; Ferraro, Gino B et al. (2018) Anti-VEGF treatment improves neurological function in tumors of the nervous system. Exp Neurol 299:326-333
Speranza, Maria-Carmela; Passaro, Carmela; Ricklefs, Franz et al. (2018) Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma. Neuro Oncol 20:225-235

Showing the most recent 10 out of 84 publications