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

CLL是西方世界最常见的白血病。在CLL中经常观察到影响细胞DNA损伤反应的核心组分（包括TP 53和ATM）的失能突变。这种DNA损伤信号网络由基于激酶的信号转导级联组成，在响应遗传毒性应激时被激活以阻止细胞周期并启动DNA修复。如果损伤程度超出修复能力，则激活导致凋亡的其他途径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途径的身份，这些途径反复改变并与CLL的预后不良和化疗耐药性相关。这些途径中包括DNA损伤响应性促凋亡ATM-p53级联，以及许多促存活途径，包括KRAS-MAPK轴，以及MYD 88驱动的NF κ B信号传导。在整个第一个资助期内，我们已经组装了许多模拟这些高风险畸变的本地小鼠模型。我们特别产生了Atm和Tp 53缺陷型以及Kras和Myd 88突变型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Chk 1和MK2的抑制剂之间存在协同相互作用，特别是在KRAS突变体环境中，我们现在将评估Kras突变型CLL是否对这种双重检查点抑制方法有反应。此外，我们将测试Myd 88突变型CLL中IRAK 1、IKK和JNK的联合抑制是否显示协同效应。最后，我们将使用一系列模拟惰性至侵袭性CLL的小鼠模型，以询问依地拉里斯、伊曲替尼和ABT-199的顺序或联合使用是否在遗传学定义的高风险CLL中显示协同药物相互作用。

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.