BET结构域抑制剂治疗多发性骨髓瘤:体内体外数据

Haematologica

2017-07-27Article

7.702

影响因子

原标题:BET溴结构域抑制剂CPI203在体外和体内多发性骨髓瘤(MM)模型中通过阻断Ikaros和MYC信号增强来那度胺和地塞米松活性

① 研究使用CPI203靶向MYC+来那度胺/地塞米松治疗多发性骨髓瘤的效果;② 结果:体外实验中,CPI203可以增强来那度胺效果,阻断MYC和Ikaros信号;即使在来那度胺/地塞米松耐药的细胞系中,CPI203也可以起到抗骨髓瘤效果;③ 在原代细胞实验中,CPI203可以增强来那度胺/地塞米松效果;④ 体内实验中,CPI203+来那度胺/地塞米松也可以减轻肿瘤负荷;⑤ 结论:BET抑制剂联合来那度胺可能在复发难治性MM患者中起到治疗效果。

BET溴结构域抑制剂 多发性骨髓瘤(MM) 地塞米松 来那度胺 小鼠模型

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Title:
The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling

DOI:
10.3324/haematol.2017.164632

Abstract & Authors展开

Abstract:
Most of patients with multiple myeloma treated with current therapies, including immunomodulatory drugs, eventually develop relapsed/refractory disease. Clinical activity of lenalidomide relies on degradation of Ikaros and the consequently reduction on IRF4 expression, both required for myeloma cell survival and involved in the regulation of MYC transcription. Thus, we sought to determine the combinatorial effect of a MYC-interfering therapy with lenalidomide/dexamethasone. We analyzed the potential therapeutic effect of the combination of BET bromodomain inhibitor CPI203 with the lenalidomide/dexamethasone regimen in myeloma cell lines. CPI203 exerted a dose-dependent cell growth inhibition in cell lines, indeed in lenalidomide/dexamethasone-resistant cells (median response at 0.5μM: 65.4%), characterized by G1 cell cycle blockade and a concomitant inhibition of MYC and Ikaros signaling. These effects were potentiated by the addition of lenalidomide/dexamethasone. Results were validated in primary plasma cells from patients with multiple myeloma co-cultured with mesenchymal stromal cell line stromaNKtert. Consistently, the drug combination evoked a 50% reduction in cell proliferation and correlated with basal Ikaros mRNA expression levels (p=0.04). Finally, in SCID mouse xenotransplant model of myeloma, addition of CPI203 to lenalidomide/dexamethasone decreased tumor burden, evidenced by a lower glucose uptake and increase in the growth arrest marker GADD45B, with simultaneous downregulation of key transcription factors such as MYC, Ikaros and IRF4. Taken together, our data show that the combination of a BET bromodomain inhibitor with a lenalidomide-based regimen may represent a therapeutic approach to improve the response in relapsed/refractory patients with multiple myeloma, even, in cases with suboptimal prior response to immunomodulatory drugs.

All Authors:
Tania Díaz,Vanina Rodríguez,Ester Lozano,Mari-Pau Mena,Marcos Calderón,Laura Rosiñol,Antonio Martínez,Natalia Tovar,Patricia Pérez-Galán,Joan Bladé,Gaël Roué,Carlos Fernández de Larrea

First Authors:
Tania Díaz

Correspondence:
Joan Bladé,Gaël Roué,Carlos Fernández de Larrea

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