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Systems Biology Analysis of Kinase Inhibitor Protein Target Profiles in Leukemia Treatments
Jacques Colinge, Head of Bioinformatics, CeMM
To be able to understand the mechanisms of action of drugs, predict their efficacy, and anticipate their potential side-effects is important during drug development. In diseases where the genetic background of patients modulates treatment response, it allows personalizing the therapy.
We have developed computational methods to analyze unbiased drug target profiles, measured by chemical proteomics, which we applied to kinase inhibitors. Chemical proteomics pulldows are affinity purification methods that measure compound-protein interactions and they have revealed that kinase inhibitors can be promiscuous compounds [1,2], hence motivating a system-wide analysis approach. We were able to correlate chemical pulldown data with disease models constructed on the basis of known causative genes by means of diffusion processes [2], e.g. random walks. In the case of chronic myeloid leukemia (CML), this allowed us to predict very likely immunosuppressive effects of bosutinib and new indications for CML drugs [3]. Recently, in still unpublished work, we measured the protein target profiles of four kinase inhibitors in two Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) cell lines. We obtained predictions of treatment efficacy in reasonable agreement with experimentally determined IC50 values and therefore were able to recommend the most successful therapy from in silico models.
Proteomics of triple-negative breast cancer
Metodi Metodiev, Biological Safety Officer, University of Essex
Triple-negative breast cancer is hard to treat because of the lack of targeted therapeutic options. The malignant cells of this type express neither the steroid hormone receptors ER and PgR, nor ErbB2, making all existing targeted therapeutic options ineffective and inappropriate [1]. This talk will present recent data obtained by genome-scale protein profiling of triple-negative tumors and SILAC-based phosphoroteomics of cultured cancer cells. The study found that CD74, a protein that is frequently overexpressed in epithelial cancers, is significantly overexpressed in the lymph node-positive tumors compared to less invasive node-negative tumors [2]. Ectopic overexpression of CD74 in an established cancer cell line, which does not express the protein normally, resulted in stimulation of cell migration and significant increase of invasion through the extracellular matrix. Phosphoproteome analysis showed that CD74 overexpression causes changes in the phosphorylation of a multitude of signalling proteins. Specific changes in the cellular localization of proteins known to be involved in cancer progression and metastasis were also observed by confocal microscopy. The results and their implications will be discussed in the context of the emerging approaches for stratified/personalized treatment of cancer in general, and for the treatment of triple-negative breast cancer in particular.
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