Development of synergistic combination regimens for the treatment of chemotherapy-resistant high-risk CLL

开发治疗耐药高危 CLL 的协同联合方案

• 批准号: 234150916
• 负责人: Professor Dr. Christian Reinhardt
• 金额: --
• 依托单位: Klinik für Hämatologie und Stammzelltransplantation
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234150916?language=en
• 关键词: Development; synergistic; combination; regimens; treatment

CLL is the most common leukemia in the western world. Disabling mutations affecting core components of the cellular DNA damage response, including TP53 and ATM, are frequently observed in CLL. This DNA damage signaling network, which consists of a kinase-based signal transduction cascade, is activated in response to genotoxic stress to arrest the cell cycle and initiate DNA repair. If the extent of damage is beyond repair capacity, additional pathways leading to apoptosis are activated to eliminate these potentially cancerous cells. In the last years, genome sequencing data revealed the identity of numerous pathways that are recurrently altered and associated with a poor prognosis and chemotherapy resistance in CLL. Among these pathways is the DNA damage-responsive pro-apoptotic ATM-p53 cascade, as well as a number of pro-survival pathways, including the KRAS-MAPK axis, as well as MYD88-driven NFkB signaling. Throughout the first funding period, we have assembled a number of autochthonous mouse models that mimic these high-risk aberrations, in vivo. We particularly generated Atm- and Tp53¬-deficient, as well as Kras- and Myd88-mutant CLL models. Building on our own preliminary data, which suggest a synergistic interaction between inhibitors of the cell cycle checkpoint kinases Chk1 and MK2 particularly in KRAS-mutant settings, we will now assess whether Kras-mutant CLLs respond to this dual checkpoint inhibition approach. In addition, we will test whether combined inhibition of IRAK1, IKK and JNK in Myd88-mutant CLLs displays synergistic effects. Lastly, we will use a series of mouse models mimicing indolent to aggressive CLL to ask whether sequential or combined use of idelalisib, ibrutinib and ABT-199 dispöays synergistic drug interaction in genetically-defined high-risk CLLs.

CLL是西方世界最常见的白血病。影响细胞DNA损伤反应核心成分的失能突变，包括TP53和ATM，在CLL中经常观察到。这种DNA损伤信号网络由一个基于激酶的信号转导级联组成，在基因毒性应激下被激活，以阻止细胞周期并启动DNA修复。如果损伤的程度超过了修复能力，导致细胞凋亡的额外途径被激活，以消除这些潜在的癌细胞。在过去的几年中，基因组测序数据揭示了许多与CLL预后不良和化疗耐药相关的反复改变的通路的身份。这些途径包括DNA损伤反应性促凋亡的ATM-p53级联，以及一些促存活的途径，包括KRAS-MAPK轴，以及myd88驱动的NFkB信号。在第一个资助期，我们在体内组装了许多模仿这些高风险异常的原生小鼠模型。我们特别建立了Atm-和Tp53 -缺陷，以及Kras-和myd88突变的CLL模型。基于我们自己的初步数据，这些数据表明细胞周期检查点激酶Chk1和MK2抑制剂之间存在协同相互作用，特别是在kras突变环境中，我们现在将评估kras突变cll是否对这种双检查点抑制方法有反应。此外，我们将测试在myd88突变cll中联合抑制IRAK1、IKK和JNK是否具有协同作用。最后，我们将使用一系列模拟惰性到侵袭性CLL的小鼠模型，以询问顺序或联合使用ideelalisib、ibrutinib和ABT-199 dispöays在遗传定义的高风险CLL中是否具有协同药物相互作用。