Identifying therapeutic targets by elucidating signaling pathways in pediatric lymphoid leukemias

Naomi Eline van der Sligte

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    Despite intensive chemotherapy, acute lymphoblastic leukemia (ALL) relapse is still a major cause of cancer-related death in children and the survival of children with lymphoid blast crisis chronic myeloid leukemia (CML-LyBC) is even worse. Further improvements in outcome, achieved by dose optimization and combination therapy, have stagnated due to chemotherapy related toxicity. Therefore, new treatment options are warranted to further improve the cure rates of these children.
    It has been hypothesized that malignant transformation of cells highly depends on deregulated kinase-mediated signal transduction pathways; intracellular signaling cascades involving protein phosphorylation events catalyzed by active kinases. In this thesis we generated insight in active signal transduction pathways using kinome profiling in pediatric lymphoid leukemias to identify potential druggable targets for future treatment strategies.
    Our kinase activity profiles revealed several signaling proteins relevant for ALL pathogenesis and of potential interest for future targeted therapy approaches. The validity of our approach was shown with the identification of RON and CREB as attractive targets for future investigations since downregulation of these targets resulted in a decreased leukemic cell growth and survival of ALL cell lines. Moreover, kinome profiles showed that within predefined lymphoid leukemic subtypes, in this thesis acute lymphoblastic leukemia patients harboring IKZF1 deletions and lymphoid blast crisis chronic myeloid leukemia patients, heterogeneous subgroups exist; challenging the implementation of kinase inhibitors. Based on this thesis we can conclude that kinome profiling, especially when implemented in a personalized medicine strategy combining kinomics, proteomics, and drug screens, is an elegant approach to bridge the gap between pediatric cancers and the use of kinase inhibitors.
    Originele taal-2English
    KwalificatieDoctor of Philosophy
    Toekennende instantie
    • Rijksuniversiteit Groningen
    Begeleider(s)/adviseur
    • de Bont, Eveline, Supervisor
    • van Leeuwen, Frank N., Co-supervisor, Externe Persoon
    Datum van toekenning30-sep.-2015
    Plaats van publicatie[Groningen]
    Uitgever
    Gedrukte ISBN's978-90-367-8074-2
    Elektronische ISBN's978-90-367-8075-9
    StatusPublished - 2015

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