# Project 4- Targeting the neuronal microenvironment in gliomas (Monje/Suva)

> **NIH NIH P50** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $305,184

## Abstract

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.

## Key facts

- **NIH application ID:** 10245089
- **Project number:** 5P50CA165962-08
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Mario Luca Suva
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $305,184
- **Award type:** 5
- **Project period:** 2013-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245089

## Citation

> US National Institutes of Health, RePORTER application 10245089, Project 4- Targeting the neuronal microenvironment in gliomas (Monje/Suva) (5P50CA165962-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10245089. Licensed CC0.

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