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

Area of Science:

• Neuro-oncology
• Cancer Therapeutics
• DNA Repair Mechanisms

Background:

• Glioblastoma (GBM) is a prevalent and aggressive primary brain tumor.
• Current treatments for GBM have limited efficacy, necessitating novel therapeutic strategies.
• 5-ethynyl-2'-deoxyuridine (EdU), a DNA labeling agent, is recognized for its interaction with nucleotide excision repair pathways.

Purpose of the Study:

• To evaluate the repurposing potential of EdU as a treatment for glioblastoma.
• To compare the efficacy of EdU against standard-of-care treatments like Temozolomide (TMZ).
• To assess EdU's effectiveness across various GBM models, including patient-derived ex vivo cultures.

Main Methods:

• In vitro cell culture assays using multiple GBM cell lines.
• In vivo orthotopic mouse models of GBM.
• Ex vivo Organotypic Brain Slice Culture (OBSC) platform using patient GBM tissues.
• Comparison of EdU efficacy with Temozolomide (TMZ).

Main Results:

• EdU demonstrated significantly lower ED50 values than TMZ in vitro across five GBM cell lines.
• EdU treatment significantly extended survival in two in vivo orthotopic GBM models.
• EdU efficacy in patient GBMs correlated with Ki-67 status, with one exception.
• The OBSC platform effectively differentiated therapeutic responses in heterogeneous patient tumors.

Conclusions:

• EdU shows potential as an anticancer therapeutic, particularly for rapidly proliferating cells, with low off-target toxicity.
• The OBSC platform is a valuable tool for assessing therapeutic efficacy on diverse patient tumor tissues.
• OBSC facilitates precision testing to identify potential responders and non-responders to EdU treatment ex vivo.