ID #95 Dual polyamine pathway blockade synergises with irinotecan to eradicate MYC-driven medulloblastoma

Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is characterised by poor survival in high-risk, MYC-amplified disease. Polyamines, essential polycations that regulate DNA and chromatin biology, are frequently elevated in aggressive cancers. We previously demonstrated that DIPGs depend on polyamine metabolism, and combined inhibition of polyamine synthesis (DFMO) and transport (AMXT-1501) produces profound survival benefit. Here we evaluated dual polyamine pathway inhibition in MYC-driven medulloblastoma and its potential to enhance chemotherapy response.

Gene-expression profiling from the ZERO Childhood Cancer Program revealed significant overexpression of polyamine regulators in medulloblastoma relative to normal foetal brain. qPCR confirmed upregulation of polyamine biosynthetic genes and downregulation of catabolic regulators, consistent with pathway activation. Dual inhibition of polyamine synthesis and transport led to synergistic suppression of cell proliferation and clonogenicity. RNA-sequencing demonstrated marked downregulation of DNA-repair pathways, functionally sensitising tumour cells to DNA-damaging agents. Co-treatment with SN-38 (active metabolite of irinotecan), at low-nanomolar doses, achieved complete eradication of tumour cells in cytotoxicity and clonogenic assays, with the strongest effects observed in MYC-amplified models. Annexin-V flow cytometry revealed significant apoptosis induction by dual-therapy, further enhanced by SN-38.

In an aggressive orthotopic MYC-driven medulloblastoma-Luc model, dual therapy significantly extended survival compared to vehicle (median 68.5 vs. 18 days; ****p<0.0001). Triple-therapy with irinotecan achieved complete tumour clearance in 7/8 mice, with histology confirming DNA-damage, apoptosis, and absence of tumour cells in long-term survivors. A second patient-derived orthotopic model is currently underway, demonstrating similar survival benefit with 100% mice in both dual/triple-therapy cohorts alive to-date, compared with complete mortality in vehicle/single-agent groups.

Targeting the polyamine pathway offers a promising, translatable therapeutic strategy for high-risk medulloblastoma. DFMO+AMXT-1501 is currently being evaluated in an ongoing Phase 1B/2A clinical trial in paediatric solid and CNS tumours. The potent synergy with irinotecan - already used in relapsed disease - warrants further clinical testing.