Project Details
Projekt
Development of synergistic combination regimens for the treatment of chemotherapy-resistant high-risk CLL
Applicant
Professor Dr. Christian Reinhardt
Subject Area
Hematology, Oncology
Term
from 2013 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 226262100
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.
DFG Programme
Clinical Research Units
