MARKERS OF PROGRESSION AND METASTASES

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Prostate cancer is the most common cancer in American men. The incidence has been increasing dramatically and the age-specific mortality rate is also increasing, though more slowly. The growing disparity between incidence and mortality may reflect the successful early detection of potentially lethal cancers. But, the prevalence of histologic cancers with low malignant potential is so high (about 4-0% in men more than 50 years old) that some cancers now being detected may be of little clinical importance. Current techniques for characterizing malignant potential clinically, before the prostate is removed, are inadequate. The biopsy specimen is not sufficiently representative of the cancer in the patient. A biopsy usually underestimates the grade, and staging studies usually underestimate the extent, so the tendency is to treat every detected cancer as potentially lethal. These are few well-established objective markers, other than grade, able to predict prognosis - either athe rate of local growth or the probability of metastasis - with sufficient accuracy for appropriate management. The purpose of this project is to develop better methods to assess the threat posed by a prostate-cancer. Our first aim is to develop better strategies for needle biopsies so that representative samples of the cancer can be obtained which accurately reflect biological potential before treatment is begun. Our second aim is to identify new markers of progression and metastatic propensity and to develop a standard efficient protocol to validate promising markers with respect to establish prognostic features and outcome. Our assessment and development of candidate markers involve a systematic approach and are based in part on a paradigm which considers that growth and metastatic potential may become uncoupled at early stages of progression. Standard statistical approaches may be inefficient at detecting complex relationships among markers and metastatic potential. These approaches may be complemented by computer intensive modeling techniques. We have previously reported a novel prognostic indicator, apoptotic index (A.I) and will continue to develop this marker for its clinical utility. We will also expand our immunohistochemical studies that indicate focal p53 positive staining combined with positive Ki-67 staining has significant prognostic potential beyond that of either marker alone. We will extent our investigations of p53, in our third aim, by using a novel molecular-biological approach, TA-cloning-SSCP analysis, which detects mutations in a small fraction of cells. We are particularly interested in genetic alterations associated with metastatic capacity. We will investigate mutation in, for example, p53 and TGF-beta receptor 2, detectable at high frequency in metastatic lesions compared to a matched primary tumor. Finally, we will use representational difference analysis (RDA) technology to find genes homozygously deleted in metastases compared to the primary tumor, which could be used as novel markers of metastatic capacity in the primary tumor.