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

DOI
https://doi.org/10.1038/s41408-024-01180-x
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 13

Abstract

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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.