KFO 286: Exploiting Defects in the DNA Damage Response for the Treatment of Chronic Lymphocytic Leukemia

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Treatment of chronic lymphocytic leukemia (CLL) is currently undergoing fundamental changes. Novel agents with limited toxicity, such as ibrutinib, idelalisib or venetoclax, target specific pathways and show impressive and durable responses. These novel agents, when used in combination with antibodies may soon completely replace chemotherapy for CLL. However, despite this impressive progress, there remains a very relevant clinical problem: resistance to these agents in genetically-defined high-risk patients. Specifically, resistance to chemotherapy and novel, targeted agents is tightly correlated with molecular defects in the DNA damage response (DDR). In addition to the previously identified defects in different DDR genes, alterations affecting the NFkB-, KRAS/MAPK- and PI3K/AKT pathways, B cell receptor (BCR)- and Toll-like receptor (TLR) signaling, as well as RNA metabolism and the splicing machinery, have recently emerged as high-risk aberrations in CLL.Building on the tools generated within the first funding period, the proposed projects aim at identifying therapeutically actionable molecular vulnerabilities associated with a functionally impaired DDR in CLL cells. Our results will enhance our understanding of CLL pathogenesis and will lead to the development of novel therapeutic approaches to tackle CLL. The CRU-286 benefits from the complementary expertise of its members. Several molecules involved in DDR signaling, or impacting on cellular outcomes upon DNA damage, were discovered or characterized within this CRU. We further benefit from a range of relevant in vivo models to study key pathways in CLL biology. Beyond the pre-existing expertise, we have strategically recruited two additional groups covering highly relevant aspects that were previously underrepresented in our consortium, namely epigenetics and mis-regulated splicing mediated through SF3B1 mutations (RP8), as well as systematic in vitro and in vivo drug screening, with a focus on targeting CLL-specific defects in the apoptotic machinery (RP7). In addition, we will focus on the molecular evolution of CLL. We have substantially invested into our bioinformatic infrastructure through the recruitment of M. Peifer, who has a longstanding interest in the clonal evolution of human malignancies. CLL is an almost ideal disease for this purpose, as tumor samples are easily accessible through simple phlebotomy and due to the fact that CLL is often a slowly proliferating disease, which allows the observation of affected individuals over a long period of time and during the course of multiple distinct lines of treatment.