Kurzfassung

Over the last decade, the hierarchic tumor hypothesis evolved to a central dogma in cancer research. The model postulates that so-called Cancer Stem Cells (CSCs) are exclusively responsible for propagation of tumor growth and seeding of distant metastasis. Further, the CSCs are believed to possess intrinsic properties of chemoresistance, whereby explaining the limitations of classical cancer therapies and owing to the promise of new cellular targets. We have recently demonstrated that CSCs...Over the last decade, the hierarchic tumor hypothesis evolved to a central dogma in cancer research. The model postulates that so-called Cancer Stem Cells (CSCs) are exclusively responsible for propagation of tumor growth and seeding of distant metastasis. Further, the CSCs are believed to possess intrinsic properties of chemoresistance, whereby explaining the limitations of classical cancer therapies and owing to the promise of new cellular targets. We have recently demonstrated that CSCs operate on a pernicious interaction of known oncogenic pathways (e.g. EGFR and SRC) with common stemness-related features such as Wnt/ beta-Catenin, NF-kB and others. These results indicate that effective therapeutic strategies should aim at both unique and common features of tumor-initiating cells. The goal of the present project is to identify novel molecular targets specifically designed to eliminate CSCs and evaluate their therapeutic efficiency. Based on our results we will develop a screening strategy to evaluate the response of CSCs to various drug treatments. First, targeting of identified CSCs pathways (e.g. NF-kB) will be investigated for therapeutic potency to deplete the CSC pool in vitro and in vivo. Subsequently, we will extend our investigations to screening strategy for compounds currently under clinical investigation for Hepatocellular Carcinoma (HCC) patients. Further, we will employ dynamic pharmacogenomics to characterize the adaptive molecular changes that occur during the course of different commonly used therapeutic regimens with a focus on the effect of CSCs to explore mechanisms of relapse formation. The obtained information will be computationally integrated with existing databases of whole transcriptome in vitro data in response to various chemotherapeutic compounds to ultimately identify molecular targets and develop novel combination treatment strategies.» weiterlesen» einklappen