Targeting the neuronal microenvironment in glioblastoma

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.