Abstract 525: From unbiased genetic screen to therapy: Combination of 5-ALA and artesunate for the treatment of primary glioblastoma multiforme

The natural compound Artemisinin and its derivative Artesunate are widely used anti-malarial drugs. Due to their cytotoxic activity, they have also been investigated as anti-cancer agents, while their precise mechanism of action and key host cell targets have remained largely elusive. Using an innovative forward genetic screening approach, we identified porphyrin biosynthesis as the critical pathway governing Artemisinin’s cytotoxicity. Genetic or pharmacological modulation of porphyrin production, e.g. by supplementation of the porphyrin precursor 5-aminolevulinic acid (5-ALA), defines Artesunate’s cytotoxicity in multiple eukaryotic cells, including human cancer cells. 5-ALA, a clinically approved photodynamic porphyrin enhancer, is used as a surgical fluorescence marker, which specifically labels tumorigenic brain areas due to differential uptake and metabolism. Combining Artesunate with 5-ALA therefore provides an additional level of selectivity towards malignant tissue. We translated the screening results into clinically relevant model systems of brain tumor development: glioblastoma models in engineered cerebral organoids, patient-derived brain tumor spheroids, and orthotopic xenograft models using freshly isolated patient cells. The 5-ALA-Artesunate combination showed a strong and selective antineoplastic activity in all three model systems. At AACR 2025 we will present a comprehensive preclinical data-package, including a new delivery system with animal pharmacokinetics and efficacy data, paving the way for the clinical application of this promising therapeutic approach. Citation Format: Michael Orthofer, Marianna Rozsova, Ferdinand Baumgartner, Barabara Kiesel, Georg Widhalm, Moritz Horn, Josef M. Penninger. From unbiased genetic screen to therapy: Combination of 5-ALA and artesunate for the treatment of primary glioblastoma multiforme [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 525.