Bladder cancer is a significant cause of morbidity and mortality in the United States. Although much is known about the natural history of bladder cancer in general, improvements in therapy are hampered by a limited understanding of the biologic aggressiveness of individual tumors. Better phenotypic characterization of tumors and/or earlier detection of recurrent disease would enhance the selection of appropriate therapy for individual patients. The lack of tumor markers which could offer a reliable prediction of tumor aggressiveness or facilitate the early detection of disease is a significant obstacle to improving the treatment of patients with this disease. Bladder cancers frequently express cellular antigens in a manner not found on normal urothelium. We hypothesize that these altered cellular antigens can be exploited to define bladder tumor phenotypes which will correlate with tumor biology, i.e., disease aggressiveness and response to therapy. Furthermore, we hypothesize that at least some of these inappropriately expressed antigens may convey a growth and/or metastatic advantage to bladder cancer cells. Functional proteins which are likely to convey such an advantage on tumor cells are the integrin alpha 6 beta 4 and the epidermal growth factor receptor (EGFR). In addition, other antigens whose function is currently unknown but are associated with high stage bladder tumors are likely to offer prognostic information. An example of this is an antigen that we have partially characterized with a monoclonal antibody (DD23) developed in my laboratory. This proposal encompasses research to be performed both in may laboratory and in partnership with collaborating investigators in the Cooperative Network for Evaluation of Prognostic Markers of Urinary Bladder Cancer. Research specific to my laboratory will evaluate the hypothesis that functional molecules convey a metastatic advantage and includes specific aims 1 and 2:
AIM 1 : Evaluate altered function of the integrin alpha 6 beta 4 in bladder cancer.
AIM 2 : Evaluate the role of EGFR in bladder cancer cell motility.
These aims will evaluate altered function of alpha 6 beta 4 (specifically, changes in the association of alpha 6 beta 4 with collagen VII) in vitro and in histologic sections of bladder tumors and will determine the role of EGFR in providing a metastatic phenotype through increased cell motility. We propose aims 3 and 4 as collaborative efforts thorough the Network:
AIM 3 : Compare the prognostic value of bladder washings with tumor specimens.
AIM 4 : Evaluation of tumor markers in advanced bladder cancer.
Aims 3 and 4 will evaluate the role of tumor markers (alpha 6 beta 4, collagen VII, EGFR, c-erbB-2, and to an antigen associated with high stage bladder cancer [antibody DD23]) in bladder cancer. In superficial tumors, it will be determined whether the assessment of functional tumor markers on histologic sections provides superior information to that available from bladder washings. The prognostic significance of these markers in advanced bladder cancer will be evaluated on cystectomy specimens. The clinical value of these markers will be determined in comparison to the current standards of stage and grade.
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