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

膀胱癌是泌尿道的第二大肿瘤，在德国每年约有28000例新诊断病例。在诊断时，约75%的肿瘤表现为非肌肉侵袭性疾病（NMIBC），其特点是进展率低，但治疗后5年内复发率为80%。因此，新的治疗策略是必要的。该建议的目的是为NMIBC患者建立临床前病毒疗法。病毒疗法，特别是溶瘤腺病毒（OAV）的使用是一种相对较新的治疗策略，目前在临床试验中主要用于不同于膀胱癌的肿瘤实体。我们开发了一种病毒疗法，它依赖于细胞癌原YB-1的表达，该原已被证明在膀胱癌中表达。在这一建议中，我们将重点关注三个方面。首先，我们将分析YB-1的表达水平以及参与YB-1表达模式调节的分子决定因素，以获得有关治疗反应的预后信息。该病毒的抗肿瘤活性不仅取决于其直接裂解癌细胞的特性，还取决于其刺激免疫系统的能力。分泌的YB-1已被证明可以模拟免疫系统。我们将详细分析病毒诱导分泌的YB-1对免疫系统的刺激作用。第三，我们将分析病毒在不同体内系统中的使用。在鸡绒毛膜尿囊膜模型（CAM）中，我们将表征病毒的溶瘤能力。我们将在scid - beige小鼠模型中分析免疫刺激活性的潜在分子机制，并在免疫功能不全的裸鼠模型中分析注射方法对肿瘤生长的影响。

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.