Targeting NFKB for glioblastoma therapy

• Applicants: Professor Dr. Rainer Glass; Joel Schick, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511521600

Aggressive brain tumors (like glioblastomas; GBM) have a relatively low incidence, but nevertheless represent a leading cause for cancer-related death since current clinical concepts for this entity remain largely palliative. GBM contain stem-like tumor cells that are highly resistant to chemo- or irradiation therapy. Furthermore, strong invasiveness and rapid tumor expansion are pathological hallmarks of GBM. Tumor parenchymal components like the blood tumor barrier, which controls bioavailability of therapeutic compounds to the brain, represent an additional obstacle for neuro-oncological care. The transcription factor NFkB is a signaling hub controlling stem-like traits of tumor cells, infiltrative growth and the induction of DNA damage responses after tumor therapy. Hence, NFkB represents an excellent therapeutic target for neoplastic disease. However, previous attempts to tackle NFkB signalling in the clinic have produced inacceptable side effects. We have recently shown that the drug Cannabidiol (CBD; which is applied in pediatric neurology as Epidiolex) therapeutically modulates the NFkB pathway and thereby has efficient anti-tumor effects against a large range of GBM. Predictive biomarkers for CBD-sensitive GBM were obtained providing a basis for translational studies. In our current project we are now performing a prospective study with human GBM biopsies to rigorously test predictive biomarkers and genetic markers for CBD-sensitive tumor in pharmacological assays. Furthermore, we investigate in vitro and in vivo models for their transcriptomic, proteomic, genomic and epigenetic characteristics to identify pharmacological compounds that have synergistic therapeutic effects together with CBD and exert anti-neoplastic effects through modulation of NFkB signalling. This project will provide new therapeutic strategies to address the broad pathological roles of NFkB in neoplastic disease.

• DFG Programme: Research Grants