Background: T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy with dismal survival rates after relapse in both adults and children. Aldo-keto reductase 1C3 (AKR1C3) is a member of the aldo-keto reductase superfamily of proteins that catalyses the reduction of carbonyl groups to secondary alcohols, which can be exploited therapeutically. T-ALL characteristically expresses high levels of AKR1C3 in contrast to B-cell ALL. ACHM-025 is a third-generation prodrug that is selectively activated by AKR1C3 to a potent nitrogen mustard-based DNA alkylating agent. Here, the therapeutic potential of ACHM-025 was assessed in preclinical models of paediatric T-ALL both as a single agent and in rationally designed combinations.
Methods: ALL patient-derived xenografts (PDXs) were previously established in immune-deficient NSG mice using established procedures. AKR1C3 expression was assessed by RNAseq, immunoblotting and intracellular flow cytometry. Cytotoxicity was evaluated by Resazurin assay after 48 h exposure to ACHM-025. Single agent in vivo efficacy of ACHM-025 (25 mg/kg via intraperitoneal injection, once weekly x 3) was evaluated in a single-mouse trial format against a panel of 25 T-ALL PDXs and responses assessed by event-free survival and stringent objective response measures. An ex vivo high-throughput screen (HTS) was carried out using a library consisting of 2,206 bioactive compounds in combination with ACHM-025 against a T-ALL PDX to identify possible synergistic combinations.
Results: The ex vivo sensitivity of a panel of 12 paediatric ALL PDXs to ACHM-025 significantly correlated with AKR1C3 protein (R2=0.76; P=0.0008) and RNA (R2=0.87; P<0.0004) expression. In vivo, ACHM-025 was well tolerated and exerted profound activity with 7/25 PDXs showing no evidence of disease at >250 days following the last treatment. ACHM-025 was also more effective against T-ALL PDXs in vivo with high AKR1C3 expression. The combination HTS revealed greater than additive interactions with several classes of drugs including inhibitors of HSPs, HDACs, CDKs and MDM2, the most promising of which are being prioritised for combination in vivo testing.
Conclusion: ACHM-025 exhibited profound in vivo activity against aggressive and chemoresistant T-ALL PDXs, synergistic interactions with several classes of drugs ex vivo, and shows strong potential as a novel targeted therapy for T-ALL.