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Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma

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收录情况： ◇ 统计源期刊 ◇ CSCD-C ◇ 卓越：领军期刊

作者：
Yang Linyu[1,2] * ; Qiu Qiang[1,2] * ; Wang Jie[1,2,3] * ; Wen Yi[1,2] * ; Li He[1,2,3] * ; Liang Rui[4] ; Feng Yunyu[1,2] ; Wang Fang[1,2] ; Lin Xiaojing[1,2] ; Tang Minghai[1,2] ; Yang Jianhong[1,2] ; Pei Heying[1,2] ; Zhao Peng[5] ; Wang Jishi[5] ; Xiang Jin[6] ; Miao Jia[6] ; Zheng Li[6] ; Tan Ke[4] ; Wang Yongsheng[6] ; Hu Yiguo[1,2] ; Chen Lijuan[1,2,4] ; Zhao Weili[7,8] ; Niu Ting[1,2,3] ;
机构： [1]1Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China [2]2Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China [3]3National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China [4]4Chengdu Zenitar Biomedical Technology Co. Ltd, Chengdu, China [5]5Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China [6]6Clinical Trial Center, West China Hospital, Sichuan University, Chengdu, China [7]7Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China [8]pôle de Recherches Sino- Fran鏰is en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China
出处：
DOI： 10.1038/s41392-025-02285-w
ISSN：

摘要：
Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory (r/r) multiple myeloma (MM) and lymphoma. Purinostat mesylate (PM), a highly selective HDAC I/II binhibitor, exhibits excellent antitumor activity in MM and lymphoma cell lines and mouse models, outperforming the pan-HDAC inhibitor panobinostat or first-line/second-line multi-drug combinations. Different from panobinostat, bulk RNA-seq analysis revealed that PM suppressed essential tumor survival factors and triggered inflammation and interferon responses. The scRNA-seq of 5TMM models further indicated that PM enhanced antitumor immunity by boosting monocyte- and T cell-mediated immune responses. In a phase I trial (NCT05526313; N = 29) of PM at doses up to 15 mg/m², treatment-related Grade ≥3 adverse events predominantly comprised hematologic toxicities: thrombocytopenia (75.9%), neutropenia (55.2%), leukopenia (41.4%), and lymphopenia (31.0%), with no dose-limiting toxicities observed. PM monotherapy achieved a disease control rate of 72.7% (8/11) and an objective response rate (ORR) of 9.1% (1/11) in r/r MM. Notably, r/r lymphoma patients showed an ORR of 61.6% (11/18), particularly reaching 63.6% (7/11) with 6 complete responses in diffuse large B-cell lymphoma (DLBCL). Treatment responders exhibited enhanced immune activation, with elevated CD3+CD8+ T cells and increased cytokine levels, such as IFN-γ and CXCL10. Overall, PM is safe and moderately effective in MM, but highly effective in lymphoma. Additionally, PM combined with pomalidomide and dexamethasone showed strong synergistic activity in r/r MM treatment. These findings support further open-label, multicenter phase Ib/IIa trials of PM combination therapy with immunomodulators for r/r MM, as well as phase II monotherapy trials for r/r DLBCL and r/r T-cell lymphoma.© 2025. The Author(s).

基金：
This project was funded by the Sichuan Province “14th Five-Year Plan” Life and Health Major Science and Technology Project (2022ZDZX0027), Key Project of Chengdu (2021-YF08-00002- GX), the Incubation Program for Clinical Trials of West China Hospital (19HXFH030), the National Natural Science Foundation of China (82104211), the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYGD23020, ZYJC21007), and National Key Research and Development Program of China (2022YFC2502600, 2022YFC2502603).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学
最新[2025]版：
大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学
第一作者：
第一作者机构： [1]1Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China [2]2Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
共同第一作者：
通讯作者：
通讯机构： [1]1Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China [2]2Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China [3]3National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China [4]4Chengdu Zenitar Biomedical Technology Co. Ltd, Chengdu, China [7]7Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China [8]pôle de Recherches Sino- Fran鏰is en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China
推荐引用方式(GB/T 7714)：
Yang Linyu,Qiu Qiang,Wang Jie,et al.Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma[J].Signal Transduction And Targeted Therapy.2025,10(1):201.doi:10.1038/s41392-025-02285-w.
APA：
Yang Linyu,Qiu Qiang,Wang Jie,Wen Yi,Li He...&Niu Ting.(2025).Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma.Signal Transduction And Targeted Therapy,10,(1)
MLA：
Yang Linyu,et al."Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma".Signal Transduction And Targeted Therapy 10..1(2025):201

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