Combinatorial Treatment of Glioblastoma with Temozolomide (TMZ) Plus 5-Ethynyl-2'-deoxyuridine (EdU)

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with incidence peaking in later life. It is commonly treated with surgery followed by administration of ionizing radiation and the DNA alkylating agent temozolomide (TMZ). Even though this regimen confers some progression-free survival, there is essentially no cure with the median survival with the standard of care being about 12 months. Currently, several alternative approaches are being developed to improve upon this outcome. We have already shown EdU alone effectively treats GBM, and we now study efficacy of TMZ+EdU combination therapy. TMZ+EdU significantly improves antitumor efficacy compared to either single-agent therapy against GBM cell lines in vitro, against three different orthotopic GBM xenograft models, and against passage-zero patient GBM tumor tissues engrafted within an organotypic brain slice culture (OBSC)-based platform. Together, these data suggest that EdU could be effective alongside standard of care TMZ in patients with GBM. STATEMENT OF SIGNIFICANCE (50-WORD)By simultaneously engaging distinct DNA repair pathways, combination of TMZ and EdU produced unprecedented survival benefits and synergistic effects in preclinical GBM models, offering a promising new avenue in the treatment of GBM.