Flash Talk and Poster Presentation 35th Lorne Cancer Conference 2023

A novel approach to the treatment of T-cell acute lymphoblastic leukaemia using the AKR1C3-activated prodrug, ACHM-025 (#34)

Cara E Toscan 1 2 , Hannah McCalmont 1 2 , Toby N Trahair 1 2 3 , Amir Ashoorzadeh 4 , Adam V Patterson 4 , Jeff B Smaill 4 , Richard B Lock 1 2
  1. School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia
  2. Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia
  3. Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, Australia
  4. Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand

Introduction. T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy that is exceptionally difficult to cure after relapse. We have recently demonstrated that T-ALL expresses significantly higher levels of the enzyme aldo-keto reductase family 1 member C3 (AKR1C3) compared with B-cell ALL (B-ALL). To exploit these findings we developed an AKR1C3-activated prodrug, ACHM-025, as a potential targeted therapy for paediatric T-ALL.

Aims. (1) Determine the in vivo efficacy and AKR1C3 selectivity of ACHM-025 against a panel of T-ALL patient-derived xenografts (PDXs); (2) Compare the in vivo efficacy of ACHM-025 with paediatric ALL standard-of-care consolidation therapy.

Methods and Results. Standard in vivo drug evaluation uses large cohorts of mice per PDX (e.g. 6 control, 6 drug treated) against a small panel of PDXs. We tested ACHM-025 using a single mouse testing format (1 control, 1 drug treated), to enable a large number of PDXs to be tested. ACHM-025 (25 mg/kg, i.p. weekly × 3) was tested against 21 T-ALL PDXs. Remarkably, 7/21 PDXs treated with ACHM-025 never reached event, over 250 days after the last treatment. ACHM-025 efficacy showed a significant correlation with basal AKR1C3 protein expression (R2=0.34; p=0.0054). Both ACHM-025 and cyclophosphamide are DNA cross-linking prodrugs. Comparing single agents, ACHM-025 (5 mg/kg, i.p. weekly × 2) was significantly more effective than cyclophosphamide (75 mg/kg, i.p. weekly × 2) with a T-C of 25.3 versus 57.4 days (p=0.0005). Next, we compared the in vivo efficacy of standard-of-care consolidation therapy (Ara-C, 6-mercaptopurine and cyclophosphamide) with the combination of Ara-C, 6-mercaptopurine and ACHM-025 against a T-ALL PDX derived from a patient at relapse. The combination of Ara-C, 6-mercaptopurine and ACHM-025 was significantly more effective than standard-of-care consolidation therapy, more than doubling survival (T-C) from 36.3 to 74.7 days (p=0.0005).

Conclusion. This study provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL, with AKR1C3 expression as a predictive biomarker of its activity.