Exploiting defects in the DNA damage response for the treatment of chronic lymphocytic leukemia

 Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. Numerous recurrent genetic aberrations, such as del(17p), TP53 mutations, as well as del(11q) and ATM mutations, but also aberrant SF3B1-, KRAS-, NOTCH1-, BCL2- and NFkB signaling are associated with resistance against chemo-immune therapy and poor prognosis. Intriguingly, the ATM-p53 pathway, which is a core pillar of the cellular DNA damage response (DDR), involved in apoptosis, cell cycle arrest and DNA repair appears to be a major target of disabling mutations in this high risk patient collective. With the introduction of novel targeted agents into our therapeutic armamentarium, such as the BTK inhibitor ibrutinib, the PI3Kd inhibitor idelalisib or the BCL2 inhibitor venetoclax (ABT-199), we are currently entering previously unchartered ground in CLL therapy. These novel agents are increasingly replacing chemotherapeutic agents. However, at least with respect to ibrutinib, idelalisib and venetoclax, alterations in the DDR network, particularly del(17p) and TP53 mutations, seem to retain their adverse prognostic impact, as the outcome of these patients is inferior compared to patients without these genetic abnormalities. Moreover, the risk for transformation into high-risk lymphoma, called Richter transformation (RT), is certainly not completely abolished and may even be enhanced when treating high-risk CLL with novel agents. We are currently only beginning to understand these mechanisms of drug resistance. However, the fact that alterations in the DDR, which ultimately mediates apoptosis and/or DNA repair, are clearly associated with resistance against the novel agents might suggest that an enhanced mutation frequency and/or an reduced capacity of apoptosis induction in these DDR-altered settings may contribute to drug resistance. Our consortium has identified a number of essential pathways and key drivers that mediate this therapeutic resistance and will work on the translation of these findings into new and improved therapeutic concepts.

 To achieve this goal, the CRU-286 will functionally characterize the defective DDR, particularly in genetically-defined high-risk CLL models and patients at a molecular level, both in vitro and in vivo. In addition, we will examine signaling pathways, such as the NFkB- and KRAS-MAPK pathways, B-cell receptor- and Toll-like receptor signaling, as well as RNA metabolism and defects in the RNA splicing machinery, as these signaling networks have recently been shown to be altered in high-risk CLL and to impact on the functional outcome of DDR signaling in CLL cells. A specific focus will be placed on recurrent genetic alterations that affect DDR signaling and define high-risk CLL cases. In addition to genomic aberrations, we will also investigate actionable epigenetic alterations. Our interest in epigenetic alterations is spurred by recent observations indicating that CLL cells display a more than 50% increase in methylation heterogeneity, compared to normal B cell samples. Intriguingly, a CLL-specifically increased variability in promoter methylation seems to be associated with a poor prognosis.

 The molecular understanding derived from our individual research programs will be translated into the development of new diagnostic and therapeutic strategies, specifically exploiting defects within the DDR network for the treatment of CLL patients. A particular emphasis will be placed on synergistic drug interactions, as combination drug regimens might prove effective in overcoming resistance against single agent approaches. The CRU exploits and combines the unique expertise in two complementary areas of research at the life science campus of the University of Cologne (UoC): 1) its internationally recognized clinical research on CLL, which is bundled and coordinated through the German CLL Study Group (GCLLSG) and 2) its outstanding basic and translational research on mechanistic details of the DDR network.

 The Clinical Research Unit-286 started its second funding period in November 2016 and is organized into 7 scientific and 2 central projects. The speaker of the CRU is Professor Michael Hallek, director of the Clinic I of Internal Medicine of the University Hospital of Cologne. The scientific coordinator of the CRU is Professor Christian Reinhardt, Clinic I of Internal Medicine of the University Hospital of Cologne.