National Center of Competence in Research - NCCR Molecular Oncology

SV 1532 (Bâtiment SV)
Station 19
CH-1015 Lausanne
Tel: +41 21 693 72 51
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CML is one of the four major types of leukemia in humans with ~4000 new cases diagnosed each year in Europe. CML became a paradigmatic disease for several reasons: CML is caused by a single genetic aberration, which causes the expression of the Bcr-Abl fusion tyrosine kinase from the t(9;22) Philadelphia Chromosome translocation (the first chromosomal aberration linked to cancer). Furthermore, Bcr-Abl is potently and specifically inhibited by imatinib (Gleevec) - the first small-molecule tyrosine kinase inhibitor (TKI) that was approved to treat a human disease. Imatinib is now the frontline therapy for CML in all disease stages and induces durable complete cytogenetic responses in many patients in the chronic phase of CML. However, a proportion of patients do not achieve an adequate response to imatinib (now commonly referred to as 'primary' imatinib resistance), depending on the disease stage where patients get diagnosed. In addition, the occurrence of 'secondary' imatinib resistance, primarily caused by point mutations in the Abl tyrosine kinase domain leads to patient relapse and disease progression and triggered the development of the second-generation inhibitors nilotinib and dasatinib that target most imatinib resistant Bcr-Abl variants. However, the general shortcomings of primary and secondary resistance especially in advanced disease stages and long-term tolerability of Bcr-Abl inhibitors remain a major clinical problem. Together with the inability of current Bcr-Abl inhibitors to target leukemia stem cells, additional targets that are critical for Bcr-Abl action need to be identified and exploited for combination therapy in order to ultimately result in a curative strategy for CML rather than maintaining patients in remission.

Bcr-Abl activates many signaling pathways, but the functional importance of individual pathway components and their hierarchy is not well understood, mainly because of a lack of selective inhibitors for individual signaling molecules. Among the limited number of signaling proteins that are critical for Bcr-Abl dependent oncogenic transformation and leukemogenesis are a few adapter proteins. These proteins are major substrates of Bcr-Abl and become heavily phosphorylated at multiple sites by Bcr-Abl. Thereby, and in conjunction with their own protein-protein interaction domains, they form assembly platforms for several proteins that coordinate the activation of important oncogenic signaling pathways, such as the MAPK- and PI3K-pathways. We aim to map adaptor protein interactions in an unbiased way using interaction proteomics and to develop high-affinity and high-specificity binding proteins (so-called monobodies) to selected protein-protein interaction domains in adaptor protein complexes. Such monobodies will be powerful tools to selectively inhibit specific protein-protein interactions and to define their contribution to signaling pathway activation, oncogenic transformation and leukemogenesis in vivo. Targeting specific protein-protein interactions in adaptor protein complexes in combination with Bcr-Abl TKIs could be of therapeutic benefit in patients with TKI resistance or suboptimal TKI responses. Due to the rapidly emerging critical role of the studied adaptor proteins in different solid tumors, the development and use of the described monobodies will serve as tools to advance the analysis of oncogenic signaling networks in other diseases beyond CML.