MOLECULAR & IMMUNOPHENOTYPIC ANALYSIS OF BLADDER TUMORS

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The objectives of this proposal are to immunophenotype and genotype human urinary bladder tumors, and to characterize existing and newly developed antibodies and molecular probes as potential tumor markers that may be of use in the diagnosis of bladder tumors, as well as to identify those of conceivable clinical value in predicting tumor behavior and response to therapy. We have focused our studies on exfoliated bladder epithelial cells to the characterization of markers to aid in early detection of tumor cells and monitoring patients affected with bladder cancer, assessing recurrence and/or progression. In addition, we have concentrated our analyses on human tumor tissues to the production and evaluation of prognostic factors aimed at determining the invasive/metastaticgenotype and phenotype of transitional cell carcinomas and their sensitivity to different therapeutic modalities, thus allowing the urologist and medical oncologist to tailor therapy. The specific aims are: (1) To identify markers of neoplastic transformation in urothelial cells to aid in the diagnosis of bladder cancer. We are developing an approach to distinguish exfoliated bladder epithelial tumor cells from other normal cells, including normal urothelium and inflammatory elements. This strategy is based on the combination of morphologic evaluation, DNA content by image analysis, phenotypic profile using urothelium tumor-associated antigens (i.e. Lewis X, M344, 19A211 and autocrine motility factor), and molecular probing (gene loci on chromosomes 9 and 15, as well as H-ras mutations) on cytologic preparations of exfoliated bladder cells. (2) To determine early and late events in the process of tumor progression in human bladder cancer, assessing the sensitivity and specificity of well characterized antibodies and molecular probes to (a) growth factor/growth factor receptors; (b) enzymes of the metastatic cascade; (c) tumor suppressor genes; (d) aberrant expression of oncogenes; and (e) cell surface differentiation antigens, including blood group related determinants. (3) To analyze the value of new markers as predictors of response to therapy and clinical outcome. This will include assessment of micrometastatic dissemination in surgical cases, the role of the multidrug resistance gene encoded P-glycoprotein as a possible mechanism for treatment failure in patients treated with systemic M-VAC chemotherapy, and modulation of the immuneresponse and fucosylated molecules during intravesical BCG therapy. (4) To collaborate with network members, NCI representatives, and other basic and clinical researchers in creating and exerting approved joint proposals to elucidate pertinent questions regarding new markers and clinical protocols for the diagnosis, prognosis and treatment of bladder cancer.