Molecular Correlates of Soy in Humans

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DESCRIPTION (provided by applicant): Soy is a promising cancer chemopreventive agent. Soy consumers appear to have a lower incidence of metastatic prostate cancer (PCa). We have shown that a soy constituent, genistein, a tyrosine kinase inhibitor, acts to antagonize metastatic behavior by increasing PCa cell adhesion, while at high concentrations it inhibits PCa cell growth. We recently completed a single dose phase I study in humans, demonstrating that genistein modulates intracellular tyrosine phosphorylation (or cell signaling) of blood cells. To further understand soy's in vivo effects, we are implementing a phase II clinical trial in which patients with PCa who are to have radical prostatectomy will be randomized to treatment (or not) with 2 mg genistein/kg/day, allowing evaluation of tissue for intermediate biomarkers. We hypothesize that treatment with soy-derived genistein will antagonize metastatic behavior of human prostate cells, will have long term effects on cell signaling, and will also effect prostate cell survival and growth. We propose the following specific aims: #1 : Determine whether soy antagonizes metastatic behavior in humans. Metastatic prostate cells can be detected by amplifying PSA specific RNA by reverse transcriptase polymerase chain reaction (RT/PCR). We will measure soy's ability to decrease circulating metastatic prostate cells in peripheral blood, as well as in operative field blood. In addition, treatment-related effects upon cellular morphology (a surrogate measure of effect upon cell adhesion) will be measured by quantitative image analysis of prostate tissue. #2: Evaluate effects of soy upon cell signaling pathways in vivo. Comparing soy-treated and control prostate tissue, changes in gene expression will be measured in adhesion-related genes (FAK and endoglin), as well as by gene array-based gene profiling. In addition, long-term effects upon cell signaling in vivo will be sought by measuring changes in protein-tyrosine phosphorylation of blood cells over time. #3: Determine whether soy modulates prostate cell survival and growth in vivo. Investigations will examine soy's effects upon a panel of biomarkers related to prostate cell viability and growth, including apoptotic index, cell-associated PCNA, p27 expression, serum PSA and serum testosterone.