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

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

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. rlock@ccia.org.au.
  • # 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.

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