Development of a YB-1 dependent Virotherapy for the treatment of non-muscle invasive bladder cancer

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Bladder cancer is the second most tumor of the urinary tract with ca 28.000 newly diagnosed cases per year in Germany. At diagnosis, around 75% of tumors present as non-muscle invasive disease (NMIBC) that is characterized with a low progression rate but with recurrence rates after therapy of 80% within 5 years. New therapeutic strategies are therefore necessary. The aim of this proposal ist he preclinical establishment of a virotherapy for patients suffering from NMIBC. Virotherapy and in particular the use of oncolytic adenoviruses (OAV) is a relatively novel therapeutic strategy that is currently tested in clinical trials mostly in tumor entities different from bladder cancer. We developed a virotherapy that is dependent on the expression of the cellular oncogen YB-1 that has been shown to be expressed in bladder cancer. In this proposal we will focus on three aspects. First, we will analyze expression level of YB-1 as well as molecular determinants that are involved in the regulation of expression patterns of YB-1 to allow prognostic information on therapy response. The anti-tumor activity of the virus not only depends on the direct lytic properties in cancer cells but also in its capacity to stimulate the immune system. Secreted YB-1 has been shown to simulate the immune system. We will analyze in detail the effect of virus induced secreted YB-1 on the stimulation of the immune system. Thirdly, we will analyze use of the virus in different in vivo systems. In a chicken chorioallantoic membrane model (CAM) we will characterize the oncolytic capacity of the virus. The underlying molecular mechanism of the immune stimulating activity will be analyzed in a SCID-Beige-mouse model and the efficacy of an instillation approach on tumor growth will be analyzed in an immune-incompetent nude mouse model.