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
{"title":"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","authors":"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":"10.1038/s41408-024-01180-x","DOIUrl":null,"url":null,"abstract":"<p>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.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":null,"pages":null},"PeriodicalIF":12.9000,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia\",\"authors\":\"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\":\"10.1038/s41408-024-01180-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>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.</p>\",\"PeriodicalId\":8989,\"journal\":{\"name\":\"Blood Cancer Journal\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.9000,\"publicationDate\":\"2024-11-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Blood Cancer Journal\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41408-024-01180-x\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Cancer Journal","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41408-024-01180-x","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
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.
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.