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

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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.