Article
作者: Toscan, Cara E ; de Bock, Charles E ; Williams, Sarah ; Yeats, Kristy L ; Lock, Richard B ; Evans, Kathryn ; Toscan, Cara E. ; Lock, Richard B. ; Zhou, Anthony ; Cai, Ruilin ; Smaill, Jeff B ; Ashoorzadeh, Amir ; Patterson, Adam V. ; Trahair, Toby N ; Gifford, Andrew J. ; Patterson, Adam V ; Doculara, Louise ; McCalmont, Hannah ; Mayoh, Chelsea ; Kosasih, Hansen J ; de Bock, Charles E. ; Henderson, Michelle J ; Xie, Jinhan ; Henderson, Michelle J. ; Yeats, Kristy L. ; Lin, Xiaojing ; Fu, Zhe ; Smaill, Jeff B. ; Kosasih, Hansen J. ; Cadiz, Roxanne ; Khalili, Faezeh ; Trahair, Toby N. ; Pickford, Russell ; Gifford, Andrew J
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.
