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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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Preclinical and first-in-human of purinostat mesylate, a novel selective HDAC I/IIb inhibitor, in relapsed/refractory multiple myeloma and lymphoma
- Date Crossref
- 23/06/2025
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Sichuan University West China Hospital pays non établi dans la noticeUniversité ou école supérieure
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State Key Laboratory of Biotherapy pays non établi dans la noticeStructure de recherche
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Guiyang Medical University pays non établi dans la noticeUniversité ou école supérieure
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West China Hospital of Sichuan University pays non établi dans la noticeÉtablissement de santé
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Affiliated Hospital of Guizhou Medical University Department of Hematology pays non établi dans la noticeÉtablissement de santé
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Ruijin Hospital Shanghai Institute of Hematology pays non établi dans la noticeÉtablissement de santé
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Shanghai Institute of Hematology pays non établi dans la noticeStructure de recherche
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Chengdu Zenitar Biomedical Technology Co. Ltd pays non établi dans la noticeEntreprise
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Laboratory of Molecular Pathology Pôle de Recherches Sino-Français en Science du Vivant et Génomique pays non établi dans la noticeStructure de recherche
West China Hospital — Sichuan University, State Key Laboratory of Biotherapy et Guiyang Medical University, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.