Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma
Abstract 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...
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Nature Publishing Group
2025-06-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02285-w |
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| author | Linyu Yang Qiang Qiu Jie Wang Yi Wen He Li Rui Liang Yunyu Feng Fang Wang Xiaojing Lin Minghai Tang Jianhong Yang Heying Pei Peng Zhao Jishi Wang Jin Xiang Jia Miao Li Zheng Ke Tan Yongsheng Wang Yiguo Hu Lijuan Chen Weili Zhao Ting Niu |
| author_facet | Linyu Yang Qiang Qiu Jie Wang Yi Wen He Li Rui Liang Yunyu Feng Fang Wang Xiaojing Lin Minghai Tang Jianhong Yang Heying Pei Peng Zhao Jishi Wang Jin Xiang Jia Miao Li Zheng Ke Tan Yongsheng Wang Yiguo Hu Lijuan Chen Weili Zhao Ting Niu |
| author_sort | Linyu Yang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-eb71f0a9b5524c6faa4913a2fc9d086c |
| institution | Matheson Library |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
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| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-eb71f0a9b5524c6faa4913a2fc9d086c2025-06-29T11:18:04ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-06-0110111410.1038/s41392-025-02285-wPreclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphomaLinyu Yang0Qiang Qiu1Jie Wang2Yi Wen3He Li4Rui Liang5Yunyu Feng6Fang Wang7Xiaojing Lin8Minghai Tang9Jianhong Yang10Heying Pei11Peng Zhao12Jishi Wang13Jin Xiang14Jia Miao15Li Zheng16Ke Tan17Yongsheng Wang18Yiguo Hu19Lijuan Chen20Weili Zhao21Ting Niu22Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityChengdu Zenitar Biomedical Technology Co. LtdDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, The Affiliated Hospital of Guizhou Medical UniversityDepartment of Hematology, The Affiliated Hospital of Guizhou Medical UniversityClinical Trial Center, West China Hospital, Sichuan UniversityClinical Trial Center, West China Hospital, Sichuan UniversityClinical Trial Center, West China Hospital, Sichuan UniversityChengdu Zenitar Biomedical Technology Co. LtdClinical Trial Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityShanghai 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 MedicineDepartment of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityAbstract 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.https://doi.org/10.1038/s41392-025-02285-w |
| spellingShingle | Linyu Yang Qiang Qiu Jie Wang Yi Wen He Li Rui Liang Yunyu Feng Fang Wang Xiaojing Lin Minghai Tang Jianhong Yang Heying Pei Peng Zhao Jishi Wang Jin Xiang Jia Miao Li Zheng Ke Tan Yongsheng Wang Yiguo Hu Lijuan Chen Weili Zhao Ting Niu 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 |
| title | Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma |
| title_full | Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma |
| title_fullStr | Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma |
| title_full_unstemmed | Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma |
| title_short | Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma |
| title_sort | preclinical and first in human of purinostat mesylate a novel selective hdac i iib inhibitor in relapsed refractory multiple myeloma and lymphoma |
| url | https://doi.org/10.1038/s41392-025-02285-w |
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