P12.24.A AG5: A NOVEL QUANTUM CLUSTER THERAPY TARGETING MITOCHONDRIA AND ANTIOXIDANT SYSTEMS IN GLIOBLASTOMA

Abstract Despite extensive efforts from drug developers, physicians, and patients, the prognosis for glioblastoma (GBM) remains one of the poorest in adult oncology. Current oncology drug development often revisits established technologies, with few truly novel treatments emerging to tackle challenging diseases like GBM. ARJUNA Therapeutics is breaking new ground with quantum cluster technology, creating a unique family of small molecules. The first of these, Ag5, consists of five silver atoms (a quantum cluster) with demonstrated drug-like qualities, including the ability to cross the blood-brain barrier. Ag5 penetrates cells and specifically catalyzes the irreversible inactivation of both glutathione and thioredoxin antioxidant systems in cancer cells, rapidly depleting mitochondrial glutathione and inducing cell death with minimal off-target effects at therapeutic doses. In collaboration with ARJUNA, the Laboratory for Precision Cancer Medicine at KU Leuven, Belgium, screened 20 patient-derived glioma stem cell lines from adult GBM tumors. Ag5 demonstrated cell-killing effectiveness at submicromolar concentrations in approximately 50% of these models, showing activity in both newly diagnosed and recurrent tumor models, as well as in cells from both the core and infiltrating regions. Importantly, tumor cell lines taken from individual patients at various disease stages retained their Ag5 sensitivity, even as they acquired resistance to radiotherapy and/or TMZ. Biomarkers defining sensitivity and resistance to Ag5 in patient-derived GBM lines have been identified, supported by promising preclinical in vivo data. Ag5 has the potential to benefit a significant proportion of GBM patients. A clinical phase 0 neuro-oncology trial at University Hospitals Leuven, Belgium, is planned to test both the biomarker and therapeutic hypothesis for Ag5 in adult GBM patients.