Despite the prevalence of white light for screening used in the clinic, it is widely assumed that the sensitivity and specificity of scoping (cystoscop, endoscopy, and colonoscopy) can be significantly improved with the use of optical contrast agents that specifically accumulate in tumors. The early detection of urinary bladder dysplasia and tumor margins of bladder transitional cell carcinomas (TCC) will result in improved patient prognosis and long-term survival. The present situation with 50-70% recurrence rate of bladder cancer shows the inadequacy of white light cystoscopy for detection and resection of the bladder cancer lesions. In this study, we propose to explore the efficacy of a novel optical imaging agent, fluorocoxib A, to selectively target cyclooxygenase-2 (COX-2) enzyme expressed in bladder cancer. The COX-2 enzyme is expressed at high levels intracellularly in tumor cells, but not in most of normal cells, which enables molecular imaging in vivo with high signal-to-noise ratios. This property defines COX-2 as an attractive imaging target for carcinomas detection. Together with colleagues from Vanderbilt University, we have conducted proof-of-principle studies that have explored the use of a new class of imaging agents targeting COX-2 to image tumors in a variety of in vivo pre-clinical settings. Encouraged that fluorocoxib A could be used to image COX-2-expressing xenograft tumors originated from human cell lines, and from canine primary K9TCC, and in dogs with naturally-occurring carcinomas, we now propose an essential series of studies that will bridge the gap between proof-of-principle and clinical use. We hypothesize that fluorocoxib A will detect overexpressed COX-2 in bladder dysplasia, carcinoma in situ, as well as TCC. Our proposed study using fluorocoxib A in mouse and canine TCC models will assist in translating this optical imaging agent into clinical applications for early detection of bladder cancer, as well for monitoring responses to therapy, tumor margins, and recurrence of bladder cancer. To evaluate our hypotheses, we propose the following specific aims to: 1) Determine the ability of fluorocoxib A to detect the early bladder neoplasias using a mouse model of nitrosamine-induced bladder cancer and to 2) Use fluorocoxib A to detect K9TCC in a dog cancer model. This proposal will lay the framework for enhanced collaborations in translational imaging science between investigators from the University of Tennessee and Vanderbilt University and impart a major impact on the scientific atmosphere of the University of Tennessee. This project will create an appropriate scientific environment to attract high-quality students into UT graduate program to successfully accomplish the proposed research. Fluorescence imaging by fluorocoxib A will allow earlier detection of urinary bladder tumors, when interventions can be more successful, as well as improve detection of TCC margins for more complete resection. Improved biomarkers for detection of urinary bladder neoplasia, which can rapidly and cost effectively be deployed into clinical populations, are critically needed.
Despite the prevalence of white light for cancer detection used in the clinic, it is widely assumed that the sensitivity and specificity of cystoscopy can be significantly improved by the optical contrast agent, fluorocoxib A that specifically accumulates in COX-2-expressing tumors. Our proposed study using fluorocoxib A in mouse and dog bladder cancer models will assist in translating this optical imaging agent into clinical applications for early detection of bladder cancer, as well for monitoring responses to therapy, tumor margins, and recurrence of bladder cancer. Improved bladder cancer detection and tumor surveillance can be rapidly and cost effectively deployed into the clinical populations, thereby improving patient's prognosis and long-termed survival.
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|Smolensky, Dmitriy; Rathore, Kusum; Cekanova, Maria (2015) Phosphatidylinositol- 3-kinase inhibitor induces chemosensitivity to a novel derivative of doxorubicin, AD198 chemotherapy in human bladder cancer cells in vitro. BMC Cancer 15:927|
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