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

K-RasV12癌基因作为生理敲入小鼠模型中肺腺癌选择性治疗的靶标

• 批准号: 25165932
• 负责人: Dr. Matthias Drosten
• 金额: --
• 依托单位: Centro Nacional de Investigaciones Oncológicas, Experimental Oncology Group
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2007-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/25165932?language=en
• 关键词: Das; RasV12; Onkogen; als; Ziel

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.

肺癌目前是整个西方世界最常见的癌症相关死亡原因。在诊断时，患者经常出现晚期疾病，从而限制了可用的治疗选择，并增加了对替代治疗的需求。在肺癌发生的多步骤过程中，K-RAS基因突变在肿瘤的发生和发展中起着非常重要的作用。此外，K-RAS突变对预后有不利影响，并与严重侵袭性生长有关。因此，本项目的目的是分析K-RAS癌基因在生理性敲入/敲除小鼠模型中维持肿瘤表型的作用。这是一种基因修饰，允许在人类肿瘤中常见的致癌K-RasV12通过Cre/loxP介导的重组从其内源启动子中随意表达。因此，这种小鼠模型与人类疾病非常相似。此外，FLP/FRT介导的重组的使用允许在肿瘤发展的不同阶段特异性地删除致癌的K-RasV12等位基因。肿瘤的生长/消退将通过现代成像技术在体内进行监测，单个肿瘤将通过免疫组织化学方法进行表征。因此，可以得出K-Ras癌基因在肺腺癌中作为选择性肿瘤靶点的作用的结论，因为与转基因小鼠模型相比，该小鼠模型在肿瘤起始和靶向治疗方面都与人类癌症非常相似。