Innovative Therapeutic Strategies Targeting the Network Architecture of Glioblastoma

Abstract

Recent discoveries concerning the network architecture of glioblastoma, including tumor microtubules and neuron-glioma synapses, have underscored critical pathways that sustain tumor growth, enhance resistance, and integrate glioblastoma with the surrounding neural environment. This review explores emerging therapeutic strategies targeting these pathways, including inhibitors of gap junctions, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and glutamate signaling, which are currently being tested in clinical trials. By consolidating these advances, this review seeks to bridge the gap between neurobiology, cancer neuroscience, and oncology, proposing novel approaches to overcome resistance and improve patient outcomes. The insights derived from this comprehensive review hold the potential to significantly influence the future management of glioblastoma.

Figure 1.

Conceptual basis for targeting GB tumor cell networks through therapeutic strategies currently being evaluated in clinical trials. MFA targets the structural integrity of GB networks by inhibiting Cx43, disrupting gap junction communication between glioma cells, and reducing TM formation. TMs are critical for GB resistance to therapy by providing essential metabolic and structural support. Perampanel disrupts the synaptic connections between glioma cells and neurons via AMPA receptors on TMs. This disruption is intended to affect neuronal signaling that promotes tumor growth and invasion. Troriluzole, gabapentin, sulfasalazine, and memantine target glutamate metabolism and signaling to address the high levels of glutamate secreted by GB cells. This approach seeks to alter neuroglial network activity that promotes tumor spread and neuronal hyperexcitability. (Adapted with permission from an illustration created by Sheena Gingerich.)

Figure 2.

Timeline of current clinical network-targeting trials in GB therapy. This figure illustrates the timeline and design of major clinical trials investigating novel therapeutic strategies for GB. The standard-of-care regimen for newly diagnosed GB consists of fractionated radiotherapy (2 Gy/day, 5 days per week, for 6 weeks) combined with daily TMZ (75 mg/m²). Following radiotherapy, six cycles of adjuvant TMZ (150–200 mg/m²; days 1–5 of a 28-day cycle) are administered. The GLUGLIO trial compares chemoradiotherapy plus glutamate-modulating agents (gabapentin, sulfasalazine, and memantine) with chemoradiotherapy alone in patients with newly diagnosed GB. The study’s primary endpoint is progression-free survival at 6 months, with secondary endpoints including overall survival, seizure control, quality of life, and cognitive function. GBM AGILE is an adaptive global platform trial designed to evaluate multiple investigational therapies for newly diagnosed and recurrent GB, with the goal of identifying treatments that improve overall survival. The study continuously generates real-time evidence and facilitates collaboration between industry, academia, and healthcare systems. Among the therapeutic agents under investigation is troriluzole, an orally administered small molecule that modulates glutamate signaling. The MecMeth study investigates the use of MFA in patients diagnosed with GB. Patients receive MFA 7–10 days prior to surgery, allowing assessment of its blood–brain barrier permeability and tumor penetration. The trial also explores its impact on GB cellular dynamics and TM-based network connectivity. The PerSurge study is a controlled clinical trial that evaluates the perioperative use of perampanel in patients with progressive GB. Patients receive the drug or placebo before and after resection, with the aim of assessing its effect on tumor cell networks and imaging-based tumor progression. Control groups, clinical and instrumental diagnostics, and the exact drug dosages have been omitted for clarity. MGMT-meth, O6-methylguanine-DNA methyltransferase–methylated; RT, radiotherapy.