Repurposing the DNA Labeling Agent EdU for Therapy against Heterogeneous Patient Glioblastoma

Abstract

Glioblastoma (GBM) is the most common type of malignant central nervous system tumor, and more than 300,000 people are diagnosed with GBM worldwide annually. Based on its recognition as damage by nucleotide excision repair, we now repurpose the DNA labeling agent 5-ethynyl-2'-deoxyuridine (EdU) as a treatment for GBM. We tested the efficacy of EdU in several different model systems, including not only GBM cell lines in in vitro cell culture and in vivo orthotopic mouse models of GBM, but also against living, uncultured tumor tissues of patients with GBM grown within our organotypic brain slice culture (OBSC) ex vivo platform. When compared with the standard-of-care drug temozolomide (TMZ) in in vitro GBM cell survival assays, EdU displayed ED50 values orders of magnitude lower than those of TMZ in all five GBM tumor lines tested. Against two in vivo orthotopic brain tumor models, EdU significantly extended survival relative to controls. EdU efficacy against a panel of patient GBMs largely correlated with the clinical Ki-67 status of each tumor, save for one tumor that remained unresponsive to treatment with both EdU and TMZ. Overall, these data suggest that (i) EdU has potential to be repurposed as an anticancer therapeutic and is especially adept at killing rapidly proliferating cells with low off-target toxicity; (ii) the OBSC platform can measure nuanced differences in efficacy of experimental therapeutics on heterogeneous patient tumor tissues; and (iii) OBSCs can continue to help identify potential responders and nonresponders to EdU treatment via functional precision testing of patient tumors ex vivo.