Recent results from the laboratory with others indicate that altered RB or p53 status and particularly both together are strong candidates to become prognostic markers for progression and overall survival in superficial and advanced bladder cancer (and likely other tumor types as well). The confirmation of these initial results could lead to these markers being used to develop different therapeutics strategies leading to improved survival in certain cases and a more conservative approach to bladder cancer therapy in others (i.e., bladder preservation). Individuals with abnormally strong nuclear RB staining have also been found to have a similarly poor prognosis as those with absent RB protein expression, although the molecular basis for this is presently unknown. In addition preliminary data suggest that small cell carcinomas of the lung (SCLCs) and atypical carcinomas can be distinguished by their RB status, which in turn has important diagnostic and therapeutic implications, since they receive different therapies.
Our Specific Aims therefore include: 1. To undertake large prospective studies on both superficial and advanced bladder cancer to determine if RB or p53 status in a given tumor and especially both together can be used as bona fide prognostic markers for tumor progression and overall survival. The possibility that RB and/or p53 status can be related to chemotherapeutic response will also be evaluated as well as whether other genes in the RB and p53 pathway including p16, p21, cyclin D1 and cyclin E. 2. To determine the mechanisms or molecular basis (? hyperphosphorylation) by which certain bladder tumors show an abnormal percentage of malignant cells with strong RB nuclear staining. 3. To determine both in cell culture and in vivo if bladder tumor lines with loss of RB function are more sensitive to radiation, which is suggested from the initial clinical results. 4. To verify in a large prospective that RB status can distinguish between SCLCs and atypical carcinomas. 5. To examine other genes in the RB pathway including p16, Cyclin D1, Cyclin E, are important in the pathogenesis of other specific tumor types in which the direct loss of RB function is rare. Immunohistochemical analysis will primarily be utilized for the prognostic and diagnostic studies based on the previous findings. However, Southern, Northern and Western analysis will also be done for certain genes and specific tumor types. In addition DNA sequencing and other molecular biology techniques will be used when appropriate as well. Routine techniques to measure cytotoxicity, and apoptosis produced by radiation both in culture and in vivo will also be utilized.
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