文章：

第三代AKR1C3激活型前药ACHM-025在侵袭性T细胞急性淋巴细胞白血病的临床前模型中根除疾病

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

原文发布日期：2024-11-06

DOI: 10.1038/s41408-024-01180-x

类型: Article

开放获取: 是

英文摘要：

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.
 

摘要翻译： 

T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血液恶性肿瘤，其高表达醛酮还原酶家族1成员C3（AKR1C3）。基于这一发现，我们开发了一种新型前药ACHM-025，它能被AKR1C3选择性激活为氮芥类DNA烷化剂。研究显示ACHM-025在T-ALL患者来源异种移植模型中具有强效体内抗肿瘤活性，并在7种PDX模型中完全消除了疾病。无论是单药治疗还是与阿糖胞苷/6-巯基嘌呤联用，ACHM-025的疗效均显著优于环磷酰胺。值得注意的是，ACHM-025与奈拉滨联合用药可治愈体内化疗耐药的T-ALL PDX模型。ACHM-025的体内疗效与AKR1C3表达水平直接相关，这为治疗反应提供了预测性生物标志物。综上，我们的研究为ACHM-025作为侵袭性T-ALL的靶向有效疗法提供了强有力的临床前证据。

原文链接：

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