Abstract 959: Targeting neuronal activity regulated neuroligin-3 dependency for high-grade glioma therapy

Abstract

Abstract Neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (Nlgn3), but the therapeutic potential of targeting Nlgn3 in glioma remains to be defined. Here, we demonstrate a striking dependence of HGG growth on microenvironmental Nlgn3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) fail to grow in Nlgn3 knock out mice. Using genetic mouse models, we illustrate that Nlgn3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of an ADAM10 inhibitor robustly blocks pGBM and DIPG xenograft growth via modulation of the tumor microenvironment. This work defines the therapeutic potential of and an effective strategy for targeting Nlgn3 secretion in the glioma microenvironment, which could prove transformative for treatment of HGG. Note: This abstract was not presented at the meeting. Citation Format: Humsa S. Venkatesh, Lydia T. Tam, Pamelyn J. Woo, Michelle Monje. Targeting neuronal activity regulated neuroligin-3 dependency for high-grade glioma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 959. doi:10.1158/1538-7445.AM2017-959