Neural Vulnerabilities in Glioblastoma: Rethinking Therapy Through Neuroactive Drug Repurposing

Glioblastoma, the most common and highly aggressive brain cancer, remains challenging to treat with limited gains in patient survival despite decades of research. Significant obstacles in developing new effective therapies for glioblastoma include the blood-brain barrier impeding drug delivery, inter- and intra-tumoral patient heterogeneity, and the lack of predictive preclinical models. Emerging insights from cancer neuroscience suggest that leveraging the neurodevelopmental and neurophysiological properties of glioblastoma may offer a new therapeutic window. In this context, neuroactive drugs (NADs) that are already approved for other central nervous system indications and can readily cross the blood-brain barrier may target these neural properties of glioblastoma through still unknown mechanisms. This review discusses existing preclinical models for glioblastoma drug discovery, explores how the tumor's neural-like behavior opens new therapeutic opportunities, and highlights the recent evidence supporting the repositioning of NADs as a paradigm shift in glioblastoma treatment.