Virtually all malignant gliomas become drug-resistant and recur after initial treatment, recurrent tumors are fatal within two-years, and no therapies exist that cure gliomas. The recognition that subpopulations of primitive cells with an oligodendrocyte precursor-like (OPC-like) phenotype capable of resisting standard therapy and contributing to recurrence, frames the question of whether adjuvant therapies designed to modify or eliminate OPC-like cells could slow the progression of glioma. Agents that force the differentiation of treatment-resistant OPC-like glioma cells, a phenomenon that requires cessation of proliferation, are compelling candidates for targeting OPC-like GSCs. Recently, it was observed that OPC proliferation was driven by activation of the M1, M3 and M4 muscarinic receptors. In another report, a large-scale drug screen designed to seek drugs to induce OPC differentiation in the context of multiple sclerosis identified a muscarinic receptor antagonist, benztropine (a.k.a. Cogentin), as a promoter of OPC differentiation and cell cycle exit. We have conducted studies in glioma cell lines supporting a role for benztropine in suppressing the development of drug-resistance to the standard glioma chemo-therapeutic temozolomide (TMZ). Upon treatment with TMZ, we identified the emergence of an OPC-like subpopulation of glioma cells identifiable by the co-expression of CD44, CD15 and PDGFRa. Treatment with pre-inhibitory doses of benztropine significantly reduced the TMZ IC50 in all glioma lines examined in association with blocking emergence of the CD44/CD15/PDGFR-positive subpopulation. Ongoing studies are designed to determine the tumor initiating potential of the CD44/CD15/PDGFR-positive subpopulation and whether benztropine will suppress the development of TMZ resistance in animal models of glioma.
Citation Format: Damian A. Almiron Bonnin, Joseph M. Howard, Alison L. Young, Mark A. Israel, Matthew C. Havrda. The muscarinic receptor antagonist, benztropine, blocks the expansion of a temozolomide resistant subpopulation of glioma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2047. doi:10.1158/1538-7445.AM2017-2047