Bladder cancer is the 5th most frequent cancer in the US1. The most common histologic type of bladder cancer is urothelial carcinoma and it presents often as non-muscle invasive (NMIBC) form. The initial treatment for NMIBC is transurethral resection (TUR). However, over 70% of these patients will develop tumor recurrence with 25% showing progression to muscle-invading disease within 5 years of TUR. Currently, intravesicular BCG-based immunotherapy and chemotherapy are widely used as adjuvant therapies after TUR, but their effectiveness is limited, due to side effects and/or the inability of therapeutic agents to penetrate the bladder mucosa. Thus there exists a dire need for new strategies as adjunct therapy for bladder cancer. Recently, the whole scale exfoliation of the superficial epithelium mediated by the bladder to reduce bacterial numbers during infection was found to be a specific mast cell (MC) mediated activity. Further it was possible to activate whole scale exfoliation of the bladder epithelium by merely administering a MC activator in the bladder lumen. Although a highly efficient re-epithelization program exists for bladder epithelium recovery, addition of a GAG layer to the exposed bladder wall soon after exfoliation was found to significantly enhance the speed and intensity of bladder recovery. In view of this ability to trigger rapid turnover of the bladder epithelium, we hypothesize that safely inducing bladder epithelial turnover is a powerful way to prevent recurrence of bladder cancer. Here we plan to Investigate if inducing epithelial turnover with MC activators in the bladder will reduce/eliminate tumors in the bladders of mice. We will also Investigate if administering a GAG matrix containing growth promoting and/or anti-inflammatory agents will accelerate reepithelization following induced epithelial loss.
Significance statement Bladder cancer is the 5th most frequent cancer in the US and there is no adequate treatment for this disease. Here we propose coopting a defense action used by the bladder to clear bacterial infections to clear cancerous cells.