CDK9 inhibition in RAS-mutated CMML

Chronic myelomonocytic leukemia (CMML) is an aggressive cancer of the hematopoietic system. Pathogenetically, it is frequently driven by mutations modifying the RAS oncogenes (RASmut). Unfortunately, current therapeutic approaches for RASmut CMML patients are insufficient. In the preliminary data of this project, we performed high-throughput drug screening and identified a novel molecular target in RASmut CMML. Pharmacological compounds targeting this gene are already available and tested in clinical trials for other cancer entities. In this project, we will follow up on these data and perform an extensive preclinical evaluation of this novel therapeutic approach. We will therefore use specific Rasmut mouse models of CMML, where we test for the efficacy and toxicity of these compounds. To strengthen the translational aspect, we will further validate these data in ex-vivo experiments using primary RASmut CMML patient specimens. Finally, we will transplant human RASmut CMML samples into immunocompromised mice and use these models as an additional treatment validation phase. In conclusion, the data generated in this project will preclinically test a novel therapeutic approach in RASmut CMML. Besides testing its feasibility, efficacy, and toxicities, the project will also aim to elaborate on the mechanisms behind this pharmacological strategy. Ultimately, we will use the data generated within this project to pave the way to the initiation of clinical trials in RASmut CMML.