第三代 AKR1C3 激活原药 ACHM-025 在侵袭性 T 细胞急性淋巴细胞白血病临床前模型中根除疾病

IF 12.9 1区 医学 Q1 HEMATOLOGY
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
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引用次数: 0

摘要

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,它表达高水平的醛酮还原酶家族1成员C3(AKR1C3)。为了利用这一发现,我们开发了一种新型原药 ACHM-025,它能被 AKR1C3 选择性地激活为氮芥 DNA 烷化剂。我们的研究表明,ACHM-025 对 T-ALL 患者衍生异种移植物(PDXs)具有强大的体内疗效,并能根除 7 个 PDXs 中的疾病。无论是作为单药还是与阿糖胞苷/6-巯基嘌呤联合使用,ACHM-025的疗效都明显优于环磷酰胺。值得注意的是,ACHM-025与奈拉拉宾联合用于治疗体内化疗耐药的T-ALL PDX时,可达到治愈效果。ACHM-025的体内疗效与AKR1C3的表达水平直接相关,为反应提供了一个预测性生物标志物。总之,我们的工作提供了强有力的临床前证据,凸显了ACHM-025作为侵袭性T-ALL靶向有效疗法的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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

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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来源期刊
CiteScore
16.70
自引率
2.30%
发文量
153
审稿时长
>12 weeks
期刊介绍: Blood Cancer Journal is dedicated to publishing high-quality articles related to hematologic malignancies and related disorders. The journal welcomes submissions of original research, reviews, guidelines, and letters that are deemed to have a significant impact in the field. While the journal covers a wide range of topics, it particularly focuses on areas such as: Preclinical studies of new compounds, especially those that provide mechanistic insights Clinical trials and observations Reviews related to new drugs and current management of hematologic malignancies Novel observations related to new mutations, molecular pathways, and tumor genomics Blood Cancer Journal offers a forum for expedited publication of novel observations regarding new mutations or altered pathways.
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