DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted October 10, 2018

James McGrath, Ph.D., University of Rochester
Joshua Meeks, M.D., Ph.D., Northwestern University
Robert Svatek, M.D., M.S.C.I. University of Texas Health San Antonio
David McConkey, Ph.D., Johns Hopkins University
Vivek Arora, M.D., Ph.D., Washington University School of Medicine

Bladder cancer is the sixth most commonly diagnosed cancer in the United States. An estimated 81,190 people will be newly diagnosed in 2018, and there will be 17,240 bladder cancer-related deaths in 2018 (1). Men are four times more likely than women to be diagnosed with bladder cancer.

Most bladder cancers originate in the wall of the bladder, which has several layers, including the transitional epithelium, connective tissue, muscle, and outermost fatty layer (2). The innermost layer, the transitional epithelium, is the most common place where bladder cancers are found; these cancers are called urothelial carcinoma (also known as transitional cell carcinoma). The urothelial cells also line the ureter (the tube from the kidneys to the bladder), the renal pelvis of the kidney, and the urethra (the tube that carries urine out of the body). Urothelial tumors may be found in all of these places within the urinary tract. Other cancers that may affect the bladder include squamous cell carcinoma (1%-2% of bladder cancers), adenocarcinoma (1% of bladder cancers), small-cell carcinoma (1% of bladder cancers), and sarcoma, that start in the muscle of the bladder.

The risk of developing bladder cancer depends on several factors, including lifestyle, environmental exposures, and family history. Smoking is a known cause for many cancers, including bladder cancer. Exposure to industrial chemicals such as aromatic amines (e.g., benzidine and beta-naphthylamine) have been implicated in bladder cancer development.

Congress included bladder cancer in the appropriation language for the Peer Reviewed Cancer Research Program (PRCRP) in Fiscal Year (FY) 2016. From FY16-FY17, the PRCRP has invested over $8 million in bladder cancer research. For FY18, Congress continues its support of bladder cancer by including it in the PRCRP. Research investment by the PRCRP into bladder cancer spans the cancer care spectrum, from early detection through treatment and survivorship.

Improving Early Detection

Dr. James McGrath
Dr. James McGrath

James McGrath, Ph.D., University of Rochester

Diagnosis of bladder cancer requires patients to undergo invasive cystoscopy and biopsy. This procedure must be used not only for detection of bladder cancer but for continued surveillance after treatment to ensure no recurrence of the tumor. Dr. McGrath’s team at the University of Rochester were awarded a FY17 Idea Award with Special Focus to characterize exosomes secreted into the urine from urothelial carcinoma cells within the bladder. These small vesicles may hold the key to non-invasive, early detection of bladder cancer. Dr. McGrath proposes to perfect a new method to efficiently capture the exosomes from human urine and distinguish exosomes derived from bladder cancer. If successful, Dr. McGrath’s investigation may lead to a non-invasive method for detection and surveillance of bladder cancer.


Improving the Standard of Care

Dr. Joshua Meeks
Dr. Robert Svatek
Dr. David McConkey

Joshua Meeks, M.D., Ph.D., Northwestern University
Robert Svatek, M.D., M.S.C.I. University of Texas Health San Antonio
David McConkey, Ph.D., Johns Hopkins University

Bacillus Calmette-Guérin (BCG) treatment is considered to be one of the first immunotherapies developed and was first hypothesized as a cancer treatment in the 1930s (3). Since its introduction to the disease in the early 1980s, BCG therapy has remained the gold standard of treatment for early-stage, non-muscle invasive bladder cancer. BCG is administered directly into the bladder via a urethral catheter, thereby limiting potential adverse effects on other cells and tissues. The mechanism by which BCG activates the immune system and the subsequent anti-cancer effects elicited by BCG are not well understood. To better understand the mechanism of BCG action, Drs. Meeks, Svatek, and McConkey were awarded a FY17 Translational Team Science Award to identify tumor-specific and immune-mediated responses that contribute to the BCG effect of killing tumor cells. The team will synergize with the global cancer research community Southwest Oncology Group (SWOG) by utilizing resources made available through S1602, a nationwide SWOG clinical trial with over 900 patients treated with BCG. The long-term goals include determining the genetic, cellular, and immune-mediated mechanisms associated with BCG therapy, designing novel therapies based on the results, and better stratifying patients’ bladder cancers to understand which patients will ultimately benefit from the therapy and perhaps identify other therapies or surveillance regimens for patients unlikely to respond to BCG.


Improving Immune Therapy

Dr. Vivek Arora

Vivek Arora, M.D., Ph.D., Washington University School of Medicine

Current immunotherapy exploits PD1, a T-cell surface protein that regulates the immune system to ensure that T cells do not kill healthy normal cells. Blockade of PD1 binding to PD-L1 leads to prolonged immune response. Immune checkpoint inhibitors target the PD1/PD1-L1 binding, thus releasing the control of T cell response and hopefully increasing the ability of the body to kill off cancer cells. Dr. Vivek Arora, with a FY17 Career Development Award, plans to better understand the factors that influence bladder cancer surveillance and sensitivity to checkpoint blockade. Through investigations into the intricacies of immune regulation, Dr. Arora will be able to delineate the factors impacting checkpoint blockade in bladder cancer and expand successful immunotherapy to more patients.

Links:

  1. https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html
  2. https://www.cancer.org/cancer/bladder-cancer/about/what-is-bladder-cancer.html
  3. https://pmj.bmj.com/content/78/922/449

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Last updated Wednesday, October 10, 2018