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Entwicklung von synergistischen Kombinationstherapien für die Behandlung von Chemotherapie-refraktären Hoch-Risiko CLLs

Fachliche Zuordnung Hämatologie, Onkologie
Förderung Förderung von 2013 bis 2021
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 226262100
 

Zusammenfassung der Projektergebnisse

During the last seven years, we have witnessed a paradigm shift in our clinical approach to CLL. The advent of novel, highly effective targeted therapeutic molecules, such as the BTK inhibitor ibrutinib, the PI3Kdelta inhibitor idelalisib or the BCL2 inhibitor venetoclax has fundamentally altered our therapeutic algorithms. Despite the undisputed clinical efficacy of the novel compounds, TP53 mutations and alterations on 17p appear to retain their adverse prognostic impact. In addition, inappropriate NFkB activity, as well as oncogenic KRAS mutations and leukemia cell-specific defects in genome maintenance and DNA repair, are emerging as potent novel predictors for adverse therapeutic response in CLL patients. Thus, the molecularly-defined spectrum of CLL cases that display an adverse prognosis, is currently being redefined through the availability of deep genomic sequencing data and the introduction of novel therapeutic agents. In the context of this CRU-286, we bundled our pharmacogenomic screening expertise and our arsenal of novel genetically-engineered mouse models of CLL to specifically focus on these newly defined high-risk CLL cases, in order to uncover novel molecular vulnerabilities specifically in this class of CLL cases. A particular focus was placed on ATM-deficient CLLs and the role of ATM in leukemogenesis and maintenance of the malignant state. Throughout the course of this CRU, we made a number of discoveries centered around targeting malignant cells that harbor well-defined defects in genome maintenance pathways, as well as oncogenic lesions that are associated with functional defects in genome maintenance. First, we generated a series of mouse models harboring various distinct malignant lesions, including CLL, lung cancer and pancreatic ductal adenocarcinoma. We employed these murine models as preclinical avatars, to demonstrate that Atm deficiency is associated with selective sensitivity against PARP1-, ATR- and DNA-PKcs inhibitors. Moreover, we could show that oncogenic Kras mutations induce endogenous genotoxic damage in affected cells. This tonic endogenous genotoxic stress created an actionable molecular dependence on the cell cycle checkpoint kinases CHK1 and MK2. We could show that inhibitors targeting these two kinases display synergistic cytotoxicity in Kras-mutant malignancies. Extending these observations, we could also show that combined inhibition of the ATR/CHK1 axis and the glucose transporter GLUT1 displays synergistic cytotoxicity in Kras-mutant cells and tumors. We also placed a specific emphasis on understanding the biological role of ATM in leukemogenesis and maintenance of the malignant state. One central observation within the second funding period was the discovery that ATM directly phosphorylates the proteasome shuttle factor UBQLN4 on Ser-318. This phosphorylation was critical for UBQLN4 to repress homologous recombination via removal of MRE11 from the damaged chromatin. Lastly, we could show that the continued absence of ATM in lymphoma cells, but also in lymphomainfiltrating T cells is critical to maintain B-NHL lymphomas, in vivo. Altogether, the work within the framework of the CRU-286 led us to a series of new discoveries, which we continue to build new research projects on.

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