Novel therapies for high-risk leukaemia in children

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Embargoed until 2020-10-01
Copyright: Karsa, Mawar
Despite remarkable improvements being made in the treatment of childhood acute lymphoblastic leukaemia (ALL), prognosis remains dismal for a certain subgroups of high-risk patients including infants with leukaemia harbouring rearrangement of the Mixed Lineage Leukaemia (MLL) gene, thus warranting development of more effective therapeutics. The approach of drug repurposing, whereby an approved drug may be applied to target a disease other than that for which it was originally intended, is one that is gaining popularity due to the potential to avoid the rising cost and lengthy process of the traditional drug discovery pathway. To identify novel candidates for high-risk leukaemia, a library of approved drugs and pharmacologically active compounds was screened against ALL cell lines with or without MLL gene rearrangement, using a cell-based viability assay. The screen identified two MLL-selective bioactive compounds. The purinergic P2Y receptor agonist and guanylate cyclase inhibitor, 2-chloroadenosine triphosphate, showed in vitro efficacy against MLL-r ALL patient-derived xenografts (PDX) whereby sensitivity was associated with decreased expression of several P2Y receptors including P2RY14, which was additionally found to be differentially expressed in MLL-r vs MLL-wt paediatric ALL patients. The second MLL-selective candidate, SID7969543 which targets Steroidogenic Factor-1 (SF-1), showed activity against a subset of MLL-r and CALM-AF10 leukaemia cell lines and synergized with etoposide and cytarabine in vitro. A subsequent secondary screen aimed at selecting more potent compounds identified two FDA-approved drugs, auranofin and disulfiram, which revealed a common ROS-mediated mechanism in potently inhibiting the viability of high-risk leukaemia cell lines and PDX in vitro. Preclinical testing of drug combinations revealed the potential of combined treatment with auranofin and cytarabine in delaying leukaemia growth in an aggressive MLL-r ALL PDX mouse model. Auranofin also demonstrated synergy with disulfiram in vitro which could be promising for future studies. In conclusion, this work identified MLL-selective compounds that uncovered potential new targetable pathways in MLL-r leukaemia for further investigation and possible future therapeutic exploitation. The two FDA-approved drugs identified highlighted the therapeutic potential of targeting the ROS pathway for high-risk leukaemia and demonstrated promising clinical utility for these patient subgroups.
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Karsa, Mawar
Henderson, Michelle
Somers, Klaartje
Lock, Richard
Sutton, Rosemary
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PhD Doctorate
UNSW Faculty
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