CSIG-20. CANNABIDIOL CONVERTS NFKB INTO A TUMOR SUPPRESSOR IN GLIOBLASTOMA WITH DEFINED ANTIOXIDATIVE PROPERTIES. (12th November 2021)

• Record Type: Journal Article
• Authors: Volmar, Marie; Cheng, Grace; Schick, Joel; Kälin, Roland; Glass, Rainer
• Is Part Of: Neuro-oncology. Volume 23: Supplement 6(2021)
• Page Start: vi37
• Page End: vi37
• Publication Date: 2021-11-12
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab196.146
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: The transcription factor NFK B drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFK B activity can suppress central oncogenic signalling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive. In a pharmacogenomics study with a panel of transgenic glioma cells we observed that NFK B can be converted into a tumor suppressor by the non-psychotropic cannabinoid Cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study we performed pharmacological assays, gene expression profiling, biochemical and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics analysis of human GBM-datasets. We found that CBD promotes DNA binding of the NFK B subunit RELA and simultaneously prevents RELA-phosphorylation on serine-311, a key residue which permits genetic transactivation. Strikingly, sustained DNA binding by RELA lacking phospho-serine 311 was fully sufficient to mediate hGSC cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen-species (ROS), while high ROS-content in other tumors blocked CBD induced hGSC death. Consequently, ROS levels served as predictive biomarker for CBD-sensitive tumors. This evidence demonstrates how a clinically approved drug can convert NFK B into a tumor suppressor and suggests a promising repurposing option for GBM-therapy