Dissertation/ Thesis
Characterization of the small molecule kinase inhibitor SU11248 (Sunitinib/ SUTENT) in vitro and in vivo ; Charakterisierung des niedermolekularen Kinase Inhibitors SU11248 (sunitinib/ SUTENT) in vitro und in vivo
| العنوان: | Characterization of the small molecule kinase inhibitor SU11248 (Sunitinib/ SUTENT) in vitro and in vivo ; Charakterisierung des niedermolekularen Kinase Inhibitors SU11248 (sunitinib/ SUTENT) in vitro und in vivo |
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| المؤلفون: | Bairlein, Michaela |
| المساهمون: | Gierl, Alfons (Prof. Dr.), Ullrich, Axel (Prof. Dr. h.c.), Schnieke, Angelika (Prof., Ph.D.) |
| بيانات النشر: | Technical University of Munich Technische Universität München |
| سنة النشر: | 2010 |
| المجموعة: | Munich University of Technology (TUM): mediaTUM |
| مصطلحات موضوعية: | info:eu-repo/classification/ddc/570, Biowissenschaften, Biologie, cancer, small molecule inhibitors, proteomics, drug target profiling, drug efficacy in vivo, response prediction, kinase therapy |
| الوصف: | SU11248 is a multitargeted kinase inhibitor approved for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors. For an optimal clinical impact of the drug and its precise response prediction in patients including adverse side-effects, drug target interaction profiles and molecular sites of action are of major importance. Using an efficient affinity chromatography based chemical proteomics approach the target spectrum of SU11248 was profiled in cancer cell lines from different tissue origins and primary mRCC tumors. 313 putative kinase targets were identified. Functional annotation of the targets revealed a diverse inhibition spectrum of SU11248 on cellular signalling processes regulating cell proliferation, survival, migration, invasion as well as energy metabolism and protein-biosynthesis. In addition, new non-kinase targets, including metabolic enzymes, were also found in the performed proteome-wide cell-based interaction screen. A direct proof of target relevance and inhibitor function could be shown by RNAi. Knock-down of high affinity targets significantly reduced SU11248 activity. Moreover, protein expression profiling showed that SU11248 sensitive cell lines are mesenchymal-like with high levels of Vimentin, compared to insensitive cell lines which are more epithelial-like, expressing high levels of E- cadherin. The expression levels of high affinity targets as well as Vimentin and E-cadherin may function as biomarkers for the prediction of SU11248 efficacy in vivo. In addition, phosphoproteomics and a SU11248 biological activity screen in cancer cell lines from different tumor types revealed a strong inhibitory impact of the drug on signalling networks within cancer cells regulating the hallmarks of cancer and potential new tumor indications suitable for SU11248 treatment in future. Taken together, the data constitute a comprehensive study of SU11248 activity and selectivity under cell physiological conditions and provide cancer-tissue specific molecular sites of action. ... |
| نوع الوثيقة: | doctoral or postdoctoral thesis |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | https://mediatum.ub.tum.de/824670; https://mediatum.ub.tum.de/doc/824670/document.pdf |
| الاتاحة: | https://mediatum.ub.tum.de/824670 https://mediatum.ub.tum.de/doc/824670/document.pdf http://nbn-resolving.de/urn:nbn:de:bvb:91-diss-20100517-824670-1-7 |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.C25B3DD6 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |