The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia
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.
Authors
- Michelle J. Henderson (ORCID: https://orcid.org/0000-0003-2741-3852)
- Roxanne Cadiz (ORCID: https://orcid.org/0009-0004-6768-8601)
- Hansen J. Kosasih (ORCID: https://orcid.org/0000-0002-0428-6195)
- Toby N. Trahair (ORCID: https://orcid.org/0000-0002-3295-228X)
- Charles E. de Bock (ORCID: https://orcid.org/0000-0001-5182-8535)
- Adam V. Patterson (ORCID: https://orcid.org/0000-0001-5138-1227)
- Richard B. Lock (ORCID: https://orcid.org/0000-0002-3436-9071)
- Xiaojing Lin (ORCID: https://orcid.org/0000-0001-5652-2703)
- Cara E. Toscan (ORCID: https://orcid.org/0000-0001-7998-0547)
- Jeff B. Smaill
- Kathryn L. Evans (ORCID: https://orcid.org/0000-0002-7884-5877)
- Russell Pickford (ORCID: https://orcid.org/0000-0001-8982-7618)
- Faezeh Khalili
- Chelsea Mayoh (ORCID: https://orcid.org/0000-0002-6398-3046)
- Andrew J. Gifford (ORCID: https://orcid.org/0000-0002-4092-2347)
- Zhe Fu (ORCID: https://orcid.org/0000-0002-3037-0286)
- Amir Ashoorzadeh (ORCID: https://orcid.org/0000-0001-8462-7879)
- Ruilin Cai
- Anthony Zhou
- Hannah McCalmont (ORCID: https://orcid.org/0000-0002-1711-8115)
- Louise Doculara
- Jinhan Xie (ORCID: https://orcid.org/0000-0001-7407-8474)
- Sarah Williams (ORCID: https://orcid.org/0000-0002-0779-6342)
- Kristy L. Yeats
Institutions
- University of Auckland (NZ)
- Malaghan Institute of Medical Research (NZ)
- Cancer Institute of New South Wales (AU)
- UNSW Sydney (AU)
- Cancer Society of New Zealand (NZ)
- Prince of Wales Hospital (AU)
- Children's Cancer Institute Australia (AU)
- Sydney Children's Hospital (AU)
- Maurice Wilkins Centre (NZ)
Publication Details
- Journal
- Blood Cancer Journal
- Published
- 2024-11-06
- DOI
- https://doi.org/10.1038/s41408-024-01180-x
- Citations
- 5
- Primary Topic
- Aldose Reductase and Taurine
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- Leukemia and Lymphoma Society
- Anthony Rothe Memorial Trust
- University of New South Wales
- Medical Research Council
- National Health and Medical Research Council