Targeting Metabolic and Epigenetic Vulnerabilities in Glioblastoma with SN-38 and Rabusertib Combination Therapy

Area of Science:

• Neuro-oncology
• Cancer Pharmacology
• Epigenetics

Background:

• Glioblastoma (GBM) is a challenging brain tumor due to heterogeneity.
• O6-methylguanine-DNA methyltransferase (MGMT) limits temozolomide efficacy in 50% of GBM patients.
• Novel therapies are crucial for overcoming treatment resistance.

Purpose of the Study:

• To investigate the metabolic and epigenetic effects of combining SN-38 and rabusertib in GBM.
• To identify synergistic drug combinations for glioblastoma treatment.

Main Methods:

• High-throughput drug screening of GBM cell lines using a cancer drug library and SN-38.
• Metabolic screening using the PEDS algorithm.
• Analysis of epigenetically relevant metabolites and glutathione cycle intermediates.

Main Results:

• Identified a synergistic combination of SN-38 and rabusertib.
• Demonstrated synergistic modulation of purine, one-carbon, and redox metabolism.
• Observed depletion of 5-methyl-cytosine, acetyl-lysine, and trimethyl-lysine, indicating epigenetic disruption.
• Reduced glutathione cycle intermediates suggested increased cellular stress.

Conclusions:

• The combination of SN-38 and rabusertib synergistically disrupts cancer cell metabolism and epigenetics.
• This combination induces cytotoxicity independent of MGMT status.
• SN-38 and rabusertib represent a promising combinatorial therapy for glioblastoma.