Metabolic specificities in chronic lymphocytic leukemia: towards the design of a new therapeutic approach

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Drug resistance remains a major cause of treatment failure in CLL. Recently, the therapeutic landscape of CLL has been dramatically modified through the introduction of targeted therapies such as ibrutinib and venetoclax, inhibitors of Bruton tyrosine kinase (BTK) and BCL2 respectively. Despite outstanding clinical results, no complete remission is guaranteed due to the arising of new resistances. Therefore, it is crucial to develop new original therapeutic approaches.

Studies of cancer cell metabolism have enjoyed a recent renaissance with the recognition that altered cell metabolism is a critical component of the tumor phenotype. This realization has brought renewed attention to Otto Warburg’s observation that cancer cells metabolize glucose in a manner that is distinct from normal cells. Warburg found that cancer cells tend to “ferment” glucose into lactate even in the presence of oxygen. This tumor characteristic is called “Warburg effect”. As a follow, the study of the solid tumor metabolism has received a notable interest in the last years and the analysis of the metabolic reprogramming has uncovered tumor cell vulnerabilities, leading to the development of combined anticancer therapeutic approaches, including the use of ritonavir (glucose uptake inhibitor), etomoxir (fatty acid b-oxidation inhibitor), or metformin (mitochondrial OXPHOS inhibitor). In contrast to that performed in solid tumors and other lymphoproliferative disorders, the analysis of the metabolic reprogramming in CLL remains still at an initial stage.

By combining bioinformatics, proteomic, ex vivo and in vivo studies, we aim to characterize the CLL B-cell metabolism that surprisingly does not follow the “Warburg effect” described above. Secondly, we explore how the molecules secreted from this microenvironment, including extracellular vesicles, can contribute to the specific metabolic profile of CLL cells. Our final goal is to propose a novel therapeutic strategy that could eliminate the CLL B cells by targeting their metabolism.