Scientific objective and rationale: The standard-of-care for patients with stage II and III bladder cancer is to undergo chemotherapy followed by bladder removal. At the time of bladder removal, 30%-40% of patients do not have identifiable tumor in their bladders. These responding patients are most often cured. Doctors and scientists do not completely understand why some tumors respond and some tumors do not. As a urologist who routinely performs bladder removal (radical cystectomy), my research has intensely focused on why patients respond to chemotherapy, and I propose to further study this in my proposal. Based on my preliminary data, I think that the immune system may be mediating the response to chemotherapy and will explore this possibility during the funding period. I have also found that several dozens of types of bacteria can be found in bladder tumors and urine from bladder cancer patients. Many of these organisms are normally found in other organs such as the bowels or mouth and have not been previously seen in the bladder or bladder cancer. I think that some of these bacteria may be able to detoxify or potentiate certain chemotherapies used in bladder cancer, thus decreasing or increasing the effectiveness of these drugs. I propose to compare the types of bacteria found in bladder cancer patients who do or do not respond to chemotherapy to determine which candidate bacteria, if any, may alter chemoresponse. The immune system and the bacteria that live in the cancerous bladder will then be manipulated in mice to test these ideas. If successful in mice, similar approaches could quickly be adopted in human trials, which I am poised to execute as a cancer scientist and bladder cancer surgeon.

PI’s Cancer Research Goals: My short-term career goal is to learn why patients respond to chemotherapy prior to having their bladder removed. This will facilitate my long-term goal to devise ways to promote chemoresponse (cure) in more patients in order to spare patients the need for bladder removal altogether.

Ultimate Applicability: This work could help us understand several previously unrecognized mechanisms contributing to chemotherapy response in bladder cancer, namely (1) activity of the immune system during response and (2) bacteria which may promote or hamper response. The immune system is increasingly recognized as a tool which can be coaxed to seek and destroy tumors. A better understanding of its role in chemoresponse will help us to better combine new immunotherapies with old chemotherapies. In addition, bacteria which are beneficial or detrimental to chemoresponse can manipulated in the bladder to stimulate responses. In fact, one commonly used therapy for bladder cancer patients is to instill a bacteria (called BCG) directly into the bladder to stimulate an immune response. Because the primary outcome of the study is the presence/absence of the tumor in the bladder (which is known immediately after surgery), the potential timeline for improvement in a clinically relevant outcome is short. Therefore, several clinical applications of this research could come promptly after conclusion of the study in the form of clinical trials to combine chemotherapy and immunotherapy, or to manipulate the bacteria present in the bladder prior to chemotherapy.

There is no risk to the patients involved in this study, because their care will not be affected. All of the studies I propose will be performed after patients have received their treatments using tissues and body fluids that were removed as part of their already-planned surgeries.

Military relevance: Bladder cancer is more common in Veterans than it is among civilians due to cancer-causing chemical exposures and tobacco consumption. It is the most expensive cancer to treat, and bladder removal is a morbid, complicated, and life-altering procedure. Identification of modifiable factors such as the immune system or bacteria which might enhance response chemotherapy could lead to cures in the absence of bladder removal surgery. These would truly be paradigm-changing discoveries.