A New Approach for the Non-Invasive Detection of Bladder Cancer

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DESCRIPTION (provided by applicant): There is an urgent need to develop an effective method for detection of primary and recurrent bladder cancer. Bladder cancer is the fourth most common malignancy in men and the ninth most common malignancy in women in Western countries. If identified early, bladder cancer is characterized by a high survival rate (94%). However, the survival rate drops significantly, to as low as 14%, if spread to other organs has occurred. Bladder cancer is also characterized by a high recurrence rate, (50% - 90%). Consequently, bladder cancer patients must undergo frequent cystoscopic surveillance. The goal of this project is to explore the feasibility of a noninvasive diagnostic test from urine that would allow early detection of new onset, as well as recurrent, bladder cancers, and which would provide an effective tool for cancer staging. Such a test, if applied to high-risk populations or surveyed patients could significantly increase survival rates, and could contribute to improved life quality and duration. Conventional diagnostic methods that involve cystoscopy and cytology are either invasive (cystoscopy), or are relatively insensitive (cytology). We propose to apply a new method based on mass spectrometry of in vitro expressed proteins (MASSIVE- PRO) that will enable detection of small fractions of mutated DNA present in the urine of bladder cancer patients. AmberGen has performed preliminary experiments that demonstrate feasibility in several key areas of this proposal. In Phase I, the MASSIVE-PRO system will be evaluated for detection of mutations in a panel of relevant genes first using mixtures of cell line DNA samples, and later using clinical samples from bladder cancer patients. The goal will be to detect mutations in Kras/Hras, FGFR3 (which are markers of low staged/low grade tumors) and p53 (which is a marker of high stage/high grade tumors) occurring at the 5% or lower level in the sample. A small set of matched tissues and urines will be provided by Dr. Kevin Loughlin, Professor of Surgery and Director of Urologic Research at Brigham and Women's Hospital (Boston, MA). During phase II, a molecular assay based on the results of Phase I will be further developed and evaluated in a clinical laboratory environment for detection of early bladder cancer. PUBLIC HEALTH RELEVANCE: There is an urgent need to develop an effective method for non-invasive detection of early stage urothelial bladder cancer, which is one of the most common cancers, and has one of the highest recurrence rates. The current standard methods for screening rely either on cytology, which has only 20% sensitivity, or on cystoscopy, which often results in false positives, and is invasive and expensive. The goal of this Phase I project is to explore the ability of a new molecular assay method based on mass spectrometry to detect early stages of urothelial bladder cancer by analyzing DNA obtained from urine for the presence of mutations in key genes associated with bladder cancer pathogenesis.