Repurposing the alcohol-deterrent drug Disulfiram for the radiotherapy of glioblastoma using an in vitro model of fractionated γ-radiation

Abstract

Glioblastoma (GB) is the most common primary brain tumor in adults. It is also one of the most lethal and devastating malignancy with a median patient survival of 14 months despite surgical resection and radiochemotherapy. Recent data has suggested that radiotherapy may trigger treatment resistance by promoting the diffuse invasive phenotype of GB, possibly through NF-kB. The alcohol-deterring drug Disulfiram was repurposed in cancer therapy for its antiinvasive properties on GB cells through NF-kB-inhibition, and is therefore an ideal combination candiate with radiotherapy. The purpose of this work is to find out whether the rational combination of Disulfiram and radiation may also have an impact on cell death and growth retardation. Establishing in a first step an in vitro model of radiotherapy, I will find evidence of distinct biological effects of the mostly used single dose radiation delivery vs. the fractionated dose delivery. In a second part, the combination treatment of Disulfiram and radiation will be investigated using the previously established model of fractionated radiation. The endpoints of cell death, growth retardation and cell cycle distribution will be considered. At last, the role of NF-kB in cell death and growth retardation after radiation and combination treatment of Disulfiram and IR will be examined.