Project information
THE STUDY OF TARGETED THERAPY IN CHRONIC LYMPHOCYTIC LEUKEMIA: REGULATION AND FUNCTION OF CD20 AND OTHER THERAPY-BASED B-CELL ANTIGENS (Veronika Šandová)

Proposed research focus to elucidate i) the mechanisms underlying CD20 regulation in the context of BTK/PI3K inhibitors treatment, and ii) to define its molecular function and interaction partners. We hypothesize that BTK inhibitors repress CD20 transcription by increasing the activity of the transcription factor FoxO1 and that ibrutinib additionally impairs IL-4-mediated activation of TAT6 by inhibiting JAK3 kinase. This proposed project has direct implications for combinatorial therapies, as CD20 molecule is utilized as a target of not only anti-CD20 monoclonal antibodies, but also in bispecific antibodies (CD20xCD3) and CAR T-cells. This central role of CD20 in the treatment of mature B cell malignancies is a strong rationale for studying its regulation and function. As the level of CD20 is downregulated by BCR inhibitors, I suggest to identify other cell-surface molecules that could be utilized as targets. In the second part of the project, I also hypothesize that alternative cell-surface targets could be identified and targeted by available monoclonal antibodies and BTK inhibitors. We conducted a comprehensive gene expression analysis of CLL samples before and after treatment with BCR inhibitors and propose a potential novel cell-surface target suitable for combinatorial therapy with BCR inhibitors. I aim to further focuson one of these targets, namely CXCR4 and to pre-clinically evaluate the anti-CXCR4 antibody ulocuplumab in combination with BTK inhibitors. All the samples for the project have been already collected and provided by Univeristy Hospital Brno based on signed MTA.