Das K-RasV12 Onkogen als Ziel einer selektiven Therapie von Adenokarzinomen der Lunge in einem physiologischen knock-in Mausmodell

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Lung cancer is currently the most common cancer-related cause of death in the entire Western World. At time of diagnosis, patients frequently present with advanced stage disease, thus limiting the available therapeutic options and increasing the need for alternative therapies. During the multi-step process of lung carcinogenesis, mutations in the K-Ras gene play an extraordinary role both for tumor initiation and progression. In addition, K-Ras mutations adversely affect prognosis and are associated with severe invasive growth. Therefore, the aim of this project is to analyze the role of K-Ras oncogenes in maintaining the neoplastic phenotype in a physiological ¿knock-in/knock-out¿ mouse model. This is characterized by a genetic modification, allowing oncogenic K-RasV12, which is frequently found in human tumors, to be expressed from its endogenous promoter through Cre/loxP-mediated recombination at will. Thereby, this mouse model closely resembles human disease. In addition, the use of Flp/frt-mediated recombination permits specific deletion of the oncogenic K-RasV12 allele at various stages of tumor development. Tumor growth/-regression will be monitored in vivo by modern imaging techniques and single tumors will be characterized immunohistochemically. Thus, conclusions can be drawn about the role of K-Ras oncogenes as selective tumor targets in lung adenocarcinomas, because in contrast to transgenic mouse models, this mouse model closely recapitulates human cancer both in terms of tumor initiation and targeted therapy.