A screening of repurposable neuroactive drugs in glioblastoma

A new study recently published on Nature Medicine screened repurposable neuroactive drugs in glioblastoma patient surgery material. The study found AP-1/BTG-mediated signalling pathway induction as a neuro-oncological glioblastoma vulnerability and showed a synergy for the anti-depressant vortioxetine with current standard-of-care chemotherapies.

Authors explored neurodevelopmental and neurophysiological vulnerabilities of glioblastoma by screening neuroactive drugs in patient-derived material with a clinically concordant and single-cell resolved platform. By profiling more than 2500 ex vivo drug responses across 27 patients and 132 drugs, researchers identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems; then, a subsequent analysis of drug–target interactions revealed AP-1/BTG-mediated signalling pathway induction as a neuro-oncological glioblastoma vulnerability, enabling expanded in silico screening of more than 1 million compounds. The anti-depressant vortioxetine emerged as a neuroactive drug synergizing with current standard-of-care chemotherapies in patients. As authors conclude, «Diverse neuroactive drugs, particularly the anti-depressant vortioxetine, target AP-1 signaling, triggering a strong neurophysiological and transcriptional response that leads to rapid glioblastoma cell death. Vortioxetine’s potency was demonstrated across modalities, with an on-target ex vivo efficacy observed in 75% of patients. Moving forward, vortioxetine in combination with standard-of-care chemotherapeutics should be tested in controlled clinical trials, potentially guided by molecular or functional patient stratification».