Somatic mutations or aberrant regulation of B-cell associated kinases such as the Spleen Tyrosin Kinase (SYK) or epigenetic regulators such as the Bromodomain and Extra-Terminal motif (BET) proteins represent promising therapeutic targets for targeted therapies in hematological neoplasias.
The dissertation aimed to evaluate SYK as a therapeutic target in human precursor cell lines of B-acute lymphoblastic leukemia (B-ALL). The following specific inhibition of SYK by Entospletinib induced anti-proliferative effects and substance-induced gene expression changes. Furthermore, a combination strategy of Entospletinib with simultaneous BET inhibition by AZD5153 (isoform-specific bivalent Inhibition) or I-BET151 (pan-BET Inhibition) was carried out in human and canine B-lymphoma cell lines. As an in vitro based approach, cell- and molecular biologic parameters were investigated after single agent- and combined exposure. Both BET single agents induced significant, dose- and time dependent anti-proliferative effects in human and canine B-lymphoma cell lines. The following combined exposure increased the anti-proliferative effects synergistically and induced a cell cycle blockade without affecting apoptosis. Whole-transcriptome analyses showed an enhanced gene expression modulation by combined SYK and BET inhibition compared to the both single agents. Furthermore, a combination-specific gene signature has been identified. Gene Ontology Enrichment analyses showed, that primarily cell biologic processes such as DNA replication and cell division were modulated by the combination.
This dissertation identified SYK as a potential therapeutic target in precursor B-ALL cell lines as well as a promising combination strategy in human and canine B-cell lymphoma cell lines. This combination approach demonstrated synergistic effects on cell biological parameters as well as a combination-specific gene modulation.