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

慢性淋巴细胞性白血病是西方世界最常见的白血病。致残性突变影响细胞DNA损伤反应的核心成分，包括TP53和ATM，在CLL中经常观察到。这个DNA损伤信号网络由一系列基于激酶的信号转导通路组成，在基因毒性应激下被激活，以阻止细胞周期并启动DNA修复。如果损伤的程度超出了修复能力，就会激活其他导致细胞凋亡的途径，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反复改变的通路的身份，这些通路与CLL预后不良和化疗耐药有关。在这些通路中，有DNA损伤反应的ATM-P53级联通路，以及包括KRAS-MAPK轴在内的许多促生存通路，以及MYD88驱动的NFkB信号通路。在整个第一个资助期，我们已经组装了一些在体内模拟这些高风险异常的本土小鼠模型。我们特别产生了ATM和TP53缺失，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抑制剂Chk1和MK2之间存在协同作用，特别是在KRAS突变的环境中，我们现在将评估Kras突变的CLL是否对这种双重检查点抑制方法做出反应。此外，我们还将测试在MyD88突变的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侵袭性CLL的小鼠模型来研究idelalisib、ibrutinib和ABT-199在基因定义的高危CLL中是否连续或联合使用药物协同作用。

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.