The overall goal of this project is to develop markers for early detection of occult urinary bladder neoplasia and its imminent progression to invasive clinically aggressive urinary bladder cancer. The core preliminary data for this proposal is provided by our genome-wide model of urinary bladder cancer progression from occult in situ preneoplastic conditions to invasive cancer. The data was generated by a strategy of whole organ histologic and genetic mapping developed in our laboratory. Using this approach we matched the patterns of genetic and molecular alterations with the natural history of disease, i.e its progression from preneoplastic conditions to invasive cancer. Our model provides data on over 30 putative tumor supressor gene loci involved in the development and progression of urinary bladder cancer. From this data, the most promising putative tumors supressor gene loci were selected for the development of markers to detect early occult urinary bladder neoplasia and its aggressive variants. In addition we hypothesize that there is a molecular mechanism of bladder cancer progression based on the amplification and overexpression of novel oncogenic kinase STK 15/BTAK responsible for genomic stability. Overexpression of this enzyme appears to be responsible for genomic instability causing abnormal segregation of chromosomes. We plan to use allelic losses in several target suppressor gene loci of chromosomes 3, 9, 10, and 13 as well as amplification/over expression of STK15/BTAK as markers for early detection of urinary bladder neoplasia and its progression to invasive clinically aggressive bladder cancer. This project should provide two major products: (1) Public repository of shared data base on all tested markers and their performance as diagnostic probes, that can be used for the development of diagnostic markers and identification of target genes not only in the urinary cancer, but in other cancer types. This data will compliment our genome wide model of bladder cancer progression and will serve as a guide for targeting tumor suppressor genes involved in bladder cancer and other cancer types. In addition, information on minimal amplified regions involving 20q amplicon will provide valuable information for markers development and for identification of dominantly activated transforming genes involved in progression of bladder cancer and possibly other cancers. (2) Diagnostically relevant panel of approximately ten FISH and ten hypervariable DNA probes for early detection of occult preneoplastic changes in the urinary bladder and their aggressive variants progressing to invasive cancer for major clinical validation trial. If this project is funded, it is the intent of our commercial partner Urocor to submit a supplemental SBIR application (letter of support from Dr. Robert W. Veltri, Vice President and General Manager of the UroSciences Group, is attached).
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