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

膀胱癌是排在第二位的尿路肿瘤，在德国每年约有28.000例新诊断病例。确诊时，约75%的肿瘤表现为非肌肉侵袭性疾病(NMIBC)，其特征是进展率低，但在5年内治疗后复发率高达80%。因此，新的治疗策略是必要的。这项建议的目的是在临床前建立一种针对NMIBC患者的病毒疗法。病毒治疗，特别是使用溶瘤腺病毒(OAV)是一种相对新颖的治疗策略，目前主要在不同于膀胱癌的肿瘤实体中进行临床试验。我们开发了一种依赖于细胞癌基因YB-1表达的病毒疗法，该基因已被证明在膀胱癌中表达。在这份提案中，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调节YB-1表达模式的分子决定因素，以提供关于治疗反应的预后信息。病毒的抗肿瘤活性不仅取决于癌细胞的直接裂解特性，还取决于其刺激免疫系统的能力。分泌型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的分泌型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情况。在鸡绒毛膜尿囊膜模型(CAM)中，我们将表征病毒的溶瘤能力。免疫刺激活性的潜在分子机制将在SCID-Beige小鼠模型中分析，而滴注方法对肿瘤生长的有效性将在免疫功能不全的裸鼠模型中分析。

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.