Blood Cancer Journal (Nov 2024)
The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia
- Cara E. Toscan,
- Hannah McCalmont,
- Amir Ashoorzadeh,
- Xiaojing Lin,
- Zhe Fu,
- Louise Doculara,
- Hansen J. Kosasih,
- Roxanne Cadiz,
- Anthony Zhou,
- Sarah Williams,
- Kathryn Evans,
- Faezeh Khalili,
- Ruilin Cai,
- Kristy L. Yeats,
- Andrew J. Gifford,
- Russell Pickford,
- Chelsea Mayoh,
- Jinhan Xie,
- Michelle J. Henderson,
- Toby N. Trahair,
- Adam V. Patterson,
- Jeff B. Smaill,
- Charles E. de Bock,
- Richard B. Lock
Affiliations
- Cara E. Toscan
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Hannah McCalmont
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Amir Ashoorzadeh
- Auckland Cancer Society Research Centre, University of Auckland
- Xiaojing Lin
- Auckland Cancer Society Research Centre, University of Auckland
- Zhe Fu
- Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland
- Louise Doculara
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Hansen J. Kosasih
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Roxanne Cadiz
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Anthony Zhou
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Sarah Williams
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Kathryn Evans
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Faezeh Khalili
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Ruilin Cai
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Kristy L. Yeats
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Andrew J. Gifford
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Russell Pickford
- Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney
- Chelsea Mayoh
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Jinhan Xie
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Michelle J. Henderson
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Toby N. Trahair
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Adam V. Patterson
- Auckland Cancer Society Research Centre, University of Auckland
- Jeff B. Smaill
- Auckland Cancer Society Research Centre, University of Auckland
- Charles E. de Bock
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- Richard B. Lock
- Children’s Cancer Institute, Lowy Cancer Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW Centre for Childhood Cancer Research, UNSW Sydney
- DOI
- https://doi.org/10.1038/s41408-024-01180-x
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 13
Abstract
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.