Oxybutynin to Inhibit Muscarinic Receptors as Adjuvant During Treatment of Diffuse Midline Glioma, H3K27-Altered (DMG, DIPG)

We analyze data indicating that a set of currently marketed FDA/EMA-approved drugs used to treat parkinsonism, extrapyramidal side effects of antipsychotic drugs, or overactive bladder may have the potential to slow the growth of glioblastoma; diffuse midline glioma, H3K27-altered (DMG); and a particular form of DMG growing in the pons of children, diffuse intrinsic pontine glioma (DIPG). These gliomas are typically associated with poor prognosis. Clinical trials evaluating conventional chemotherapeutic drugs have failed to improve DIPG survival. Our analysis of the biochemistry and physiology of DMG and DIPG concludes that neuronal acetylcholinergic agonisms at muscarinic receptors M1 and M3 on primitive oligodendrocyte precursor cells (OPCs) are trophic, growth-stimulating factors in DMG/DIPG growth. A set of muscarinic receptor inhibitors—benztropine, biperiden, and trihexyphenidyl—is used clinically to treat Parkinson’s disease or the parkinsonian side effects from antipsychotic medicines. Another muscarinic inhibitor, oxybutynin, is used to treat overactive bladder. All four drugs may impose dose-related side effects inherent to muscarinic receptor inhibition, such as xerostomia, asthenia, and mild cognitive impairment. We recount the evidence for the inhibition of OPC proliferation and migration mediated by these four M1/M3 inhibitors and report details on the rationale for selecting oxybutynin as the primary candidate for adjuvant therapy in DMG/DIPG. We chose oxybutynin as the first choice to study in DMG and DIPG compared to other antimuscarinic drugs based on its (i) high brain-tissue concentration, (ii) relatively stronger M3 inhibition, (iii) lower side-effect propensity than scopolamine, (iv) wide availability, and (v) the absence of H1 antihistamine or dopaminergic effects. Given the rapidly fatal nature of DMG and DIPG, the potential of oxybutynin for growth slowing may outweigh the associated risks and mild side-effect burdens.