# Targeting the neuronal microenvironment in glioblastoma

> **NIH NIH U19** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $169,207

## Abstract

Summary
An emerging body of data draws attention to the central role of the nervous system in pathogenesis of
glioblastoma. In preliminary studies our own group has discovered that glioblastoma integrates into normal
neural circuits, and that neuronal activity drives glioblastoma growth and progression through direct
glutamatergic synapses between neurons and glioblastoma cells and by paracrine growth factors secreted by
glutamatergic synapses. In turn, glioblastoma cells secrete glutamate to increase the excitability and
consequently the activity of neurons. This glutamate-fueled, forward-feeding cycle presents a potential drug
target. We hypothesize that targeting glutamatergic signaling broadly to disrupt these neuron – glioblastoma
interactions will decrease neuronal hyperexcitability, decrease neuron-to-glioblastoma signaling and decrease
glioblastoma growth. This hypothesis makes testable predictions that can be assessed using troriluzole – a
brain penetrant drug in advanced phase clinical trials for neurological and neuropsychiatric diseases.
 In preclinical studies, we find that troriluzole decreases glutamate in the glioblastoma
microenvironment and increases survival in a murine model of glioblastoma. Going forward, our study plan has
two specific aims. We propose (Aim one) to test troriluzole in patient-derived orthotopic xenograft (PDOX)
models of IDH WT glioblastoma, and (Aim two) to conduct a surgical window-of-opportunity clinical trial of
troriluzole in adult subjects with recurrent IDH WT glioblastoma. We will assess effects of troriluzole on
glioblastoma electrophysiology in both preclinical models and in the surgical window-of-opportunity trial using
intraoperative electrocorticography to determine the effects of troriluzole on neuronal hyperexcitability.
Glutamate and drug levels will be measured in both xenograft tissue and in resected human glioblastoma
tissue using mass spectrometry imaging; glutamate levels will be further assessed in human subjects using
perioperative microdialysis and magnetic resonance spectrometry imaging. We will examine the PDOX tissue
and resected human tissue for biomarkers of neuron-glioblastoma signaling, including levels of neuroligin-3
and phosphorylated AMPA receptors (an indicator of synaptic signaling in glioblastoma through a subtype of
glutamate receptor). We will assess effects of troriluzole on glioblastoma proliferation in both GBM PDOX
models and in resected human tumor tissue, and will measure overall survival in the preclinical models and
progression-free survival in the clinical trial. Together, these studies will elucidate the efficacy of troriluzole to
decrease glutamatergic signaling in the glioblastoma microenvironment and disrupt these pathogenic neuron-
glioblastoma interactions that robustly promote glioblastoma progression.

## Key facts

- **NIH application ID:** 10306231
- **Project number:** 1U19CA264504-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Michelle Monje-Deisseroth
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $169,207
- **Award type:** 1
- **Project period:** 2021-09-21 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10306231

## Citation

> US National Institutes of Health, RePORTER application 10306231, Targeting the neuronal microenvironment in glioblastoma (1U19CA264504-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10306231. Licensed CC0.

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