The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia

  • Blood Cancer J. 2024 Nov 6;14(1):192. doi: 10.1038/s41408-024-01180-x.
Cara E Toscan  1 ,  Hannah McCalmont  1 ,  Amir Ashoorzadeh  2  3 ,  Xiaojing Lin  2  3 ,  Zhe Fu  3  4 ,  Louise Doculara  1 ,  Hansen J Kosasih  1 ,  Roxanne Cadiz  1 ,  Anthony Zhou  1 ,  Sarah Williams  1 ,  Kathryn Evans  1 ,  Faezeh Khalili  1 ,  Ruilin Cai  1 ,  Kristy L Yeats  1 ,  Andrew J Gifford  1  5 ,  Russell Pickford  6 ,  Chelsea Mayoh  1 ,  Jinhan Xie  1 ,  Michelle J Henderson  1 ,  Toby N Trahair  1  7 ,  Adam V Patterson  2  3 ,  Jeff B Smaill  2  3 ,  Charles E de Bock  #  1 ,  Richard B Lock  #  8
Affiliations
  • 1. Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia.
  • 2. Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.
  • 3. Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland, New Zealand.
  • 4. Malaghan Institute of Medical Research, Wellington, New Zealand.
  • 5. Anatomical Pathology, NSW Health Pathology, Prince of Wales Hospital, Randwick, NSW, Australia.
  • 6. Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia.
  • 7. Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
  • 8. Children's Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia. [email protected].
  • # Contributed equally.
PMID: 39505850 DOI: 10.1038/s41408-024-01180-x
Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that expresses high levels of the enzyme aldo-keto reductase family 1 member C3 (AKR1C3). To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent. We show that ACHM-025 has potent in vivo efficacy against T-ALL patient-derived xenografts (PDXs) and eradicated the disease in 7 PDXs. ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-172314
    ACHM-025
    98.06%, Anti-tumor Agent
    Research Areas: Cancer