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

对于高风险非肌层浸润性膀胱癌患者，膀胱内BCG滴注是标准治疗。BCG通过诱导局部炎症提供抗炎作用。在大约三分之一的患者中，治疗失败，疾病可能进展为需要根治性手术的肌肉浸润性膀胱癌。迄今为止，尚未建立BCG反应的预测性生物标志物。在这方面，一个潜在的影响因素可能是患者的微生物组，通过应用特定的培养方法，不仅在肠道中，而且在尿液中都可以检测到。多项研究评估了肠道微生物组对不同肿瘤实体（特别是胃肠道恶性肿瘤）的预后、肿瘤生物学和治疗的影响。相比之下，肠道和尿液中的微生物组对膀胱癌肿瘤生物学的影响仍然是未知的。因此，我们项目的目的是调查微生物组在确定非肌肉浸润性膀胱癌高危患者对BCG治疗的反应中的作用：最初，我们计划表征和比较BCG反应和无反应患者的尿液微生物组以及肠道微生物组。在它们的鉴定之后，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类器官一起孵育来评估各个患者组中的特异性体外细胞因子应答。此外，肠道微生物组在膀胱癌发展中的肿瘤生物学作用将在gnotobiotic小鼠中进行评估。对于所有涉及的子步骤，不列颠哥伦比亚省大学及其附属实验室都具有高水平的专业知识。该项目将评估微生物组在膀胱内BCG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.