PO-405 Repositioning existing drugs as novel therapeutics for high-risk paediatric leukaemia

Abstract

IntroductionDespite remarkable improvements made in the treatment of childhood acute lymphoblastic leukaemia (ALL), prognosis remains dismal for a certain subgroups of high-risk (HR) patients including infants with leukaemia harbouring rearrangement of the Mixed Lineage Leukaemia (MLL/KMT2A) gene. Development of more effective, less toxic therapeutics is therefore urgently needed. The aim of this study was to identify compounds that target HR leukaemia cells based on drug-repurposing, whereby an approved drug is applied to treat a disease other than the one for which it was originally intended.Material and methodsNew Select A phenotypic screen was performed against HR leukaemia cell lines with a tailored compound library of 3707 approved drugs and pharmacologically active compounds.Results and discussionsThe screen identified that two FDA-approved drugs, auranofin and disulfiram, originally developed for treatment of rheumatoid arthritis and chronic alcoholism respectively, had preferential cytotoxicity against leukaemia cell lines compared to solid tumours and normal cells (p<0.0001). Both compounds subsequently showed potent activity in paediatric high-risk leukaemia patient-derived xenograft (PDX) cells cultured in vitro, including xenografts derived from MLL-rearranged ALL and Philadelphia-positive ALL subtypes. The compounds induced apoptosis within 12 hours of treatment through an increase in intracellular reactive oxygen species (ROS) (p<0.01), which was accompanied by induction of Nrf2, a master regulator of the antioxidant response. Incubation with ROS scavenger N-acetyl cysteine prior to treatment with either drug prevented the increase in cellular ROS levels (p<0.05) and rescued cells from apoptosis (p<0.0001). The drugs showed synergy with each other, and auranofin also potentiated the established chemotherapeutic cytarabine in resistant HR leukaemia cells (p=0.016).ConclusionIn summary, we have identified two FDA-approved drugs that demonstrated potent, synergistic anti-leukaemia activity through ROS induction as well as chemosensitise cells that are resistant to current chemotherapeutics, potentially opening up new avenues for clinical treatment of HR paediatric leukaemia. We will be testing these therapies in vivo using relevant PDX models of HR paediatric ALL.