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Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma.
Ricolinostat,第一个选择性组蛋白去乙酰化酶 6 抑制剂,与硼替佐米和地塞米松联合治疗复发或难治性多发性骨髓瘤。

摘要

Purpose: Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation.Experimental Design: We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase II dose in combination with standard proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1-5 and 8-12 of each 21-day cycle.Results: Single-agent ricolinostat therapy resulted in neither significant toxicity nor clinical responses. Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematologic, gastrointestinal, and constitutional toxicities compared with published data on nonselective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at ≥160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes.Conclusions: At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy. Clin Cancer Res; 23(13); 3307-15. ©2017 AACR.

译文

目的: 组蛋白去乙酰化酶 (HDAC) 抑制提高蛋白酶体抑制对多发性骨髓瘤的疗效,但增加了实质性毒性。临床前模型表明,观察到的协同作用是由于 HDAC6 通过蛋白质降解的攻击组/自噬途径介导对蛋白酶体抑制的抗性。实验设计: 我们进行了 HDAC6-selective 抑制剂 ricolinostat 的 I/II 期试验,以确定安全性、初步疗效和推荐的 II 期剂量与标准蛋白酶体抑制剂治疗相结合。复发或难治的多发性骨髓瘤患者在每个 21 天周期的第 1-5 天和第 8-12 天接受口服利索林他。结果: 单药利库林他治疗既没有产生明显的毒性,也没有产生临床反应。硼替佐米和地塞米松的联合治疗在剂量增加期间耐受性良好,但在一个扩大的队列中导致剂量限制性腹泻,每日两次,剂量为 160 毫克。与已发表的非选择性 HDAC 抑制剂的数据相比,在第二个扩展队列中,每日 160 mg 的利可诺他剂量的联合治疗耐受性良好,严重的血液学、胃肠道和体质毒性更小。在 ≥ 160 mg 的情况下,与每日 ricolinostat 联合使用的总有效率为 37%。硼替佐米难治性患者对联合治疗的有效率为 14%。治疗期间采集的样本显示外周血淋巴细胞中乙酰化微管蛋白的剂量依赖性增加。结论: 在推荐的第二阶段剂量为每天 160 毫克的利索林他,与硼替佐米和地塞米松的联合使用是安全的、耐受性良好的和积极的, 提示 HDAC6 的选择性抑制是一种有前途的多发性骨髓瘤治疗方法。Clin Cancer Res; 23 (13); 3307-15。©2017 AACR。

Histone deacetylase 6

内分泌 临床研究术语
概述  :  

组蛋白脱乙酰酶6是一类酶,即从ε-N-乙酰赖氨酸氨基酸上删除乙酰基(O=C-CH3)的组蛋白,使组蛋白更紧密地包裹DNA。这很重要,因为DNA包裹在组蛋白周围,并且DNA的表达受乙酰化和脱乙酰化的调节,其作用与组蛋白乙酰转移酶相反。组蛋白脱乙酰酶蛋白现在也称为赖氨酸脱乙酰基酶(KDAC),用以描述其功能而不是其靶标,后者还包括非组蛋白。 功能 组蛋白修饰:组蛋白尾部通常由于其赖氨酸和精氨酸氨基酸上存在胺基而带正电。这些正电荷帮

histone   英 /'hɪstəʊn/   美 /'hɪston/

释    义   n. [生化] 组蛋白

例    句   HISTONE: Histones are crucial in the process of condensing and packing DNA within a cell’s nucleus.组蛋白:组蛋白对于凝结和进一步合成细胞核内的DNA的过程必不可少。

 

deacetylase

释    义   n. 脱乙酰酶

例    句   To reverse the memory loss, doctors inject a compound called a histone deacetylase inhibitor.为了逆转记忆遗失,医生在复合物中添加了组蛋白脱乙酰基酶抑制物。

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