Abstract 5438: Exploring glioblastoma pharmacotherapy with an anti-epileptic drug: Multi-omic insights and tumor xenograft studies

Abstract Glioblastoma multiforme (GBM) remains one of the most aggressive brain tumors, with a 5-year survival rate of only 6%. GBM resistance to standard-of-care therapies underscores the need for novel treatment approaches. Metabolic reprogramming is a promising hallmark of cancer, indicating a therapeutic avenue. Lactate dehydrogenase (LDH) is upregulated in GBM and adversely affects the survival of GBM patients. In this study, we investigated the repurposing potential of a putative LDH inhibitor Stiripentol (STP), an FDA-approved anti-epileptic drug, to inhibit GBM progression. Using various in vitro biological assays and 3D spheroid assays, STP treatment demonstrated a reduction in GBM cell viability and growth. However, the precise mechanism of STP’s anticancer activity remains unclear. We aimed to elucidate STP's molecular mechanism and metabolic alterations underlying its anticancer activity in GBM. Additionally, we studied the efficacy of STP through in vivo tumor xenograft model. We adopted a multi-omics approach consisting of transcriptomics and metabolomics coupled with bioinformatic analyses. Our results from transcriptomics showed significant alterations in genes such as ALDH1A3, SERPINB2, AOX1, FGF1, TRIM22 and others involved in several biological processes such as oxidoreductase activity, extracellular membrane binding and response to DNA damage. Our metabolomic analysis demonstrated highly dysregulated metabolite enrichment in the Warburg effect, pentose phosphate pathway, glycolytic pathway, and homocysteine degradation upon STP treatment. Our metabolic and transcriptomic analysis bridges the mechanistic gap into the oxidoreductive stress and DNA damage response upon STP treatment. Our tumor xenograft studies showed significant efficacy of STP with decreased tumor volume and tumor weight. Our future studies will further elucidate the mechanistic basis of STP effects in GBM. Taken together, our findings suggest that STP has potential as a novel therapeutic lead for GBM that merits further validation and optimization to enhance its efficacy. This research was supported by an award from the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R16GM145557 and by funds from the College of Pharmacy and Health Sciences, St. John’s University, NY Citation Format: Anjali Yadav, Shraddha P. Bhutkar, Vikas V. Dukhande. Exploring glioblastoma pharmacotherapy with an anti-epileptic drug: Multi-omic insights and tumor xenograft studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5438.