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

AI Article Synopsis

  • T-cell acute lymphoblastic leukemia (T-ALL) is a severe blood cancer characterized by high levels of the enzyme AKR1C3.
  • A new prodrug called ACHM-025 was developed, which activates specifically through AKR1C3 to produce a potent cancer-fighting agent.
  • ACHM-025 demonstrated strong effectiveness in eliminating T-ALL in patient-derived models, outperforming standard treatments, especially when used in combination therapies.

Article 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542020PMC
http://dx.doi.org/10.1038/s41408-024-01180-xDOI Listing

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