OS05.6.A POLYAMINE PATHWAY BLOCKADE SENSITISES MYC-DRIVEN MEDULLOBLASTOMA TO CHEMOTHERAPY

Abstract BACKGROUND Medulloblastoma is a cerebellar tumour and the most common malignant paediatric brain cancer, comprising over 20% of childhood CNS neoplasms. It is highly invasive and frequently disseminates early. Polyamines—small polycations involved in DNA replication, translation, and cell proliferation—are frequently upregulated in cancer to meet the enhanced metabolic and biosynthetic demands of rapidly dividing tumour cells. We previously demonstrated that diffuse intrinsic pontine glioma (DIPG), an incurable brainstem tumour, critically depends on polyamine metabolism. Inhibition of polyamine synthesis with DFMO, a clinically safe ODC1 inhibitor, showed limited efficacy alone; however, compensatory activation of polyamine transport led us to combine it with a transport inhibitor (AMXT 1501). This dual blockade produced unprecedented survival in aggressive DIPG models and sensitised neuroblastoma to chemotherapy. This study aimed to assess the efficacy of dual polyamine pathway inhibition in MYC-driven medulloblastoma and its potential to enhance chemotherapy. METHODS AND RESULTS Gene expression profiling of CNS tumours from the ZERO childhood cancer program revealed significant overexpression of polyamine regulators in paediatric medulloblastoma compared to normal foetal brain. Dual inhibition of the polyamine pathway led to potent, synergistic suppression of medulloblastoma cell proliferation and clonogenicity. RNA-sequencing revealed substantial downregulation of DNA-repair pathways following treatment, functionally sensitising cells to DNA-damaging agents. The addition of SN-38 (active metabolite of irinotecan), even at low nanomolar concentrations, resulted in complete tumour eradication in both cytotoxicity and clonogenic survival assays, with the most pronounced effects observed in MYC-amplified medulloblastoma cells. Apoptosis, assessed via Annexin V flow cytometry, was significantly increased with dual treatment and further enhanced by SN-38. In vivo efficacy was assessed in an aggressive orthotopic MYC-driven medulloblastoma-Luc model. Dual therapy significantly extended survival compared to vehicle (median survival: 68.5 vs. 18 days; ****p<0.0001), while triple therapy with irinotecan achieved complete tumour eradication in 7 out of 8 mice. Histological analysis confirmed increased DNA damage and apoptosis, with no detectable proliferative tumour cells in the surviving animals. CONCLUSION Targeting the polyamine pathway represents a promising, clinically translatable strategy across aggressive paediatric brain tumours. Synergy with irinotecan—a chemotherapeutic already used in relapsed medulloblastoma—underscores the translational relevance of this approach, which is currently being evaluated in an ongoing Phase 1B/2A clinical trial in children with solid tumours, including CNS malignancies.