The muscarinic receptor drug trihexyphenidyl can alter the growth of mesenchymal glioblastomas in vivo

Provisionally accepted

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Transcriptomics-based tumor subtype classification has established the mesenchymal lineage of GBM (MES-GBM) as a cancer with particularly aggressive behavior and high resistance to therapy. Previously, trihexyphenidyl (THP), a marketed oral drug targeting the muscarinic M1 receptor, was shown to suppress the proliferation and survival of GBM stem cells of the classical transcriptomic subtype. In a series of in vitro experiments, this study confirms the therapeutic potential of THP by effectively suppressing the growth, proliferation and survival of MES-GBM cells while having limited effects on non-tumor cells. Transcriptomic profiling of treated cancer cells identified genes and associated metabolic pathways as potential underlying molecular mechanisms responsible for the effects induced by THP. In vivo studies of THP in immunocompromised mice bearing orthotopic MES GBMs demonstrated a moderate response to the drug. This study further highlights the potential of repurposing THP as a treatment regimen for anti-cancer, however the mode of action and optimal treatment protocols for in vivo regimens need to be further investigated.