The role of urinary microbiome in determining response to intravesical BCG-therapy in patients with high risk non-muscle invasive bladder cancer.

对于高危非肌肉浸润性膀胱癌患者，膀胱内灌注卡介苗代表了治疗的标准。卡介苗通过诱导局部炎症起到抗肿瘤作用。在大约三分之一的患者中，治疗失败，疾病可能会进展为肌肉浸润性膀胱癌，需要进行根治性手术。到目前为止，还没有建立起卡介苗反应的预测生物标志物。在这方面，一个潜在的影响因素可能是病人的微生物群，这种微生物群不仅可以在肠道中检测到，而且可以通过应用特定的培养方法在尿液中检测到。多项研究评估了肠道微生物组对不同肿瘤实体的预后、肿瘤生物学和治疗的影响，特别是在胃肠道恶性肿瘤中。相比之下，肠道和尿液中的微生物群对膀胱癌肿瘤生物学的影响仍是广为人知的。因此，我们项目的目的是调查微生物组在决定卡介苗治疗高危非肌肉浸润性膀胱癌患者疗效中的作用：首先，我们计划表征和比较卡介苗反应和无反应患者的尿液微生物组和肠道微生物组。在鉴定后，将通过将微生物组与肿瘤细胞系、膀胱上皮细胞以及患者来源的肿瘤器官孵育来评估各自患者组中的特异性细胞因子反应。此外，有关肿瘤生物学的肠道微生物组在膀胱癌发展中的作用将在灵生小鼠中进行评估。对于所有涉及的子步骤，不列颠哥伦比亚大学以及附属实验室都可以找到高水平的专业知识。该项目将评估微生物组在膀胱内卡介苗治疗反应中的作用，以全面了解其治疗和预测潜力。

For patients with high-risk non-muscle invasive bladder cancer, intravesical BCG instillation represents the standard-of-care. BCG provides an antineoplastic effect by inducing local inflammation. In approximately one third of the patients, the therapy fails and the disease may progress to a muscle-invasive bladder cancer requiring radical surgery. Predictive biomarkers for BCG response have not been established so far. In this regard, a potential influencing factor could be the patient’s microbiome which is detectable not only in the intestine but also in the urine by the application of specific cultivation methods. Multiple studies have evaluated the influence of the gut microbiome regarding prognosis, tumor biology and therapy of different tumor entities, particularly in gastrointestinal malignancies. In contrast, the impact of the microbiome, both in the gut and in the urine, on tumor biology of the bladder cancer remains widely unknown. Therefore, the aim of our project is the investigation of the microbiome’s role in determining the response to a BCG therapy in high-risk patients with non-muscle invasive bladder cancer: Initially, we plan to characterize and compare the urinary microbiome as well as the gut microbiome in BCG-responsive and non-responsive patients. After their identification, the specific in vitro cytokine response in the respective patient groups will be evaluated by incubation of the microbiome with tumor cell lines, bladder epithelial cells as well as patient-derived tumor organoids. Moreover, the role of the intestinal microbiome regarding tumor biology in the development of bladder cancer will be evaluated in gnotobiotic mice.For all addressed sub-steps, a high level of expertise can be found in the University of British Columbia as well as in the affiliated laboratories. The project will evaluate the role of the microbiome in the response to intravesical BCG therapy to obtain a comprehensive understanding of its therapeutic and predictive potential.