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Pharmacodynamics and proteomic analysis of acalabrutinib therapy: similarity of on-target effects to ibrutinib and rationale for combination therapy.
Leukemia ( IF 11.4 ) Pub Date : 2018-Apr-01 , DOI: 10.1038/leu.2017.321
V K Patel , B Lamothe , M L Ayres , J Gay , J P Cheung , K Balakrishnan , C Ivan , J Morse , M Nelson , M J Keating , W G Wierda , J R Marszalek , V Gandhi

Acalabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, is associated with high overall response rates and durable remission in previously treated chronic lymphocytic leukemia (CLL); however, complete remissions were limited. To elucidate on-target and pharmacodynamic effects of acalabrutinib, we evaluated several laboratory endpoints, including proteomic changes, chemokine modulation and impact on cell migration. Pharmacological profiling of samples from acalabrutinib-treated CLL patients was used to identify strategies for achieving deeper responses, and to identify additive/synergistic combination regimens. Peripheral blood samples from 21 patients with relapsed/refractory CLL in acalabrutinib phase I (100-400 mg/day) and II (100 mg BID) clinical trials were collected prior to and on days 8 and 28 after treatment initiation and evaluated for plasma chemokines, reverse phase protein array, immunoblotting and pseudoemperipolesis. The on-target pharmacodynamic profile of acalabrutinib in CLL lymphocytes was comparable to ibrutinib in measures of acalabrutinib-mediated changes in CCL3/CCL4 chemokine production, migration assays and changes in B-cell receptor signaling pathway proteins and other downstream survival proteins. Among several CLL-targeted agents, venetoclax, when combined with acalabrutinib, showed optimal complementary activity in vitro, ex vivo and in vivo in TCL-1 adoptive transfer mouse model system of CLL. These findings support selective targeting and combinatorial potential of acalabrutinib.

中文翻译:

acalabrutinib治疗的药效学和蛋白质组学分析:目标作用与ibrutinib的相似性以及联合治疗的原理。

Acalabrutinib是一种高度选择性的Bruton酪氨酸激酶抑制剂,与先前治疗的慢性淋巴细胞性白血病(CLL)的高总体缓解率和持久缓解相关。但是,完全缓解是有限的。为了阐明acalabrutinib的靶向作用和药效学作用,我们评估了几个实验室终点,包括蛋白质组学变化,趋化因子调节和对细胞迁移的影响。来自接受acalabrutinib治疗的CLL患者的样品的药理学分析用于确定实现更深层反应的策略,并确定加法/协同组合方案。在治疗开始前和治疗后第8天和第28天收集了21例acalabrutinib I期(100-400 mg / day)和II期(100 mg BID)复发/难治性CLL患者的外周血样本,并评估了血浆趋化因子,反相蛋白质阵列,免疫印迹和假经验。在测量acalabrutinib介导的CCL3 / CCL4趋化因子产生变化,迁移测定以及B细胞受体信号通路蛋白和其他下游生存蛋白的变化方面,acalabrutinib在CLL淋巴细胞中的靶向药效学特征与ibrutinib相当。在几种靶向CLL的药物中,当与acalabrutinib联合使用时,venetoclax在CLL的TCL-1过继转移小鼠模型系统中显示出最佳的体外,离体和体内互补活性。
更新日期:2017-11-03
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