研究定义的遗传途径淋巴瘤的难以治疗的形式

研究在The University of Texas MD Anderson Cancer Center已经阐明的新颖致癌途径并指向使用BET抑制剂的用于治疗的困难性治疗形式的信息淋巴瘤。

188bet体育网址发现是在科学转化医学在网上公布。

The study, led byMichael Green, Ph.D.，助理教授Lymphoma & Myeloma, showed that transcription factor 4 (TCF4) is the most frequent genetic alteration in activated B-cell-like diffuse large B-cell lymphoma (ABC-like DLBCL), and may be amenable to therapeutic targeting with bromodomain-inhibiting drugs called BET-inhibitors.

DLBCL是淋巴瘤的最常见的形式，并且在使用的组合化疗和免疫方案，R-CHOP 60％患者治疗。亚型ABC状DLBCL与基本上更坏的结果，当第一线治疗失败相关联的患者。

Improving lymphoma treatment

“DLBCL can be successfully treated, but therapies are needed for those who relapse, or are refractory to current treatments,” said Green. “Our team found that a percentage of ABC-like DLBCL patient tumors had copy gains on part of chromosome 18, which increased TCF4 expression, which in turn, activated immunoglobulin M (IgM) and MYC. These findings suggest that targeting TCF4 may hold promise against ABC-like DLBCL.”

A common avenue for tumorigenesis is the gain or loss of DNA encoding oncogenes or tumor suppressor genes. Green’s team found that tumors with chromosome 18 gains were dependent on TCF4 and that TCF4 was regulated by bromodomain protein BRD4. They then tested bromodomain inhibition in xenograft mouse models and reported reduced tumor growth and enhanced survival.

科学家确定TCF4的减小是通过BET抑制减少了IgM和MYC表达和诱导细胞凋亡在ABC样DLBCL细胞与TCF4 DNA拷贝数增益的机制之一。

特别是，绿看着ARV771的BET降解剂，并且发现肿瘤ARV771处理的小鼠分别为显著小，具有减少BRD4，TCF4，IgM和MYC表达的水平。他们的研究结果表明，该分子可达到足够的浓度肿瘤部位具有功能效果。

“有这些小鼠中没有毒性的迹象，并与ARV771治疗与生存的显著延长相关，”格林说。“我们的数据提供了在抑制BET一个明确的理由ABC状DLBCL和表明ARV771是消除TCF4及其靶基因和治疗ABC-像在体外和体内DLBCL细胞系有效。这些发现强调了这种与未来的临床研究潜在影响淋巴瘤的新的遗传基础。”