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

  • Int J Mol Sci. 2025 Jan 8;26(2):474. doi: 10.3390/ijms26020474.
Jennifer Chiou  1  2 ,  Valeria Impedovo  1  2 ,  Yen Bao Huynh  1  2 ,  Ruggiero Gorgoglione  1  2 ,  Luiz O F Penalva  3  4 ,  Alessia Lodi  1  2 ,  Andrew J Brenner  5 ,  Stefano Tiziani  1  2  6  7
Affiliations
  • 1. Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, TX 78712, USA.
  • 2. Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA.
  • 3. Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA.
  • 4. Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA.
  • 5. Mays Cancer Center, UT Health San Antonio, 7979 Wurzbach Road, San Antonio, TX 78229, USA.
  • 6. Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA.
  • 7. Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX 78723, USA.
PMID: 39859189 DOI: 10.3390/ijms26020474
Abstract

Glioblastoma (GBM), the most prevalent primary malignant brain tumor, remains challenging to treat due to extensive inter- and intra-tumor heterogeneity. This variability demands combination treatments to improve therapeutic outcomes. A significant obstacle in treating GBM is the expression of O6-methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces the efficacy of the standard alkylating agent, temozolomide, in about 50% of patients. This underscores the need for novel, more targeted therapies. Our study investigates the metabolic-epigenetic impact of combining SN-38, a novel Topoisomerase Inhibitor inducing DNA double-strand breaks, with rabusertib, a checkpoint kinase 1 inhibitor. We identified this synergistic combination through high-throughput drug screening across a panel of GBM cell lines using a Cancer drug library combined with SN-38. A secondary metabolic screening with the PEDS algorithm demonstrated a synergistic modulation of purine, one-carbon, and redox metabolism. Furthermore, the combined treatment led to the significant depletion of epigenetically relevant metabolites such as 5-methyl-cytosine, acetyl-lysine, and trimethyl-lysine. Reduced intermediates of the glutathione cycle indicated increased cellular stress following combinatorial treatment. Overall, the combination of SN-38 and rabusertib synergistically disrupts metabolites associated with epigenetic adaptations, leading to cytotoxicity independent of O6-methylguanine-DNA methyltransferase status, thereby underpinning this combination as a promising candidate for combinatorial therapy in GBM.

Keywords
SN-38; epigenetics; glioblastoma; high-throughput drug screening; liquid chromatography–high resolution tandem mass spectrometry; metabolomics; rabusertib; subcellular metabolism.
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