The objective of the program project is to develop a novel mechanism-driven strategy for prostate cancer prevention. The approach is based on suppressing androgen signal transduction at two different steps simultaneously by using finasteride to inhibit the formation of dihydrotestosterone and selenium to reduce androgen receptor (AR) expression. The program is built along a bench-to-bedside paradigm and consists of three highly integrated projects. Project 1 is to delineate how finasteride and selenium work cooperatively to modulate certain molecular events in controlling the clonal expansion of prostate cancer cells. Special emphasis is placed on the functional analysis of key targets and pathways responsible for the induction of apoptosis following treatment with finasteride/selenium. Microenvironmental hypoxia is frequently seen in a colony of proliferating cancer cells due to abnormalities of the vasculature. It is well known that hypoxia produces a variety of molecular changes as a selective pressure for survival. There is recent evidence suggesting that hypoxia facilitates AR activation and the transcription of androgen-responsive genes. The above process is mediated by a redox-regulating protein called peroxiredoxin-1, or Prx1. Prx1 is preferentially elevated in prostatic intraepithelial neoplasia and prostate cancer cells. Project 2 is to investigate the mechanism of hypoxia/Prxl stimulation of AR signaling and to assess the role of Prx1 in modifying the cancer control efficacy of finasteride/selenium. The findings of Projects 1 and 2 are critical to the interpretation of the clinical trial results of Project 3. A short-term intervention trial is proposed to verify the effect of finasteride/selenium on androgen target gene expression and apoptosis induction in prostate tissue samples obtained from pre-prostatectomy patients. A second objective of the trial is to determine whether a high level of Prx1 diminishes the sensitivity to finasteride/selenium intervention. Every year, approximately 230,000 new cases of prostate cancer are diagnosed in the US, and some 30,000 men will die of this disease. As a public health problem, prostate cancer engenders huge medical care and human suffering costs. Blocking the progression of small volume, low-grade neoplasia is increasingly being recognized as an important aspect of prostate cancer control. Our goal is to find a way of managing the disease at an early stage in order to prevent it from becoming clinical relevant. ? ? ?
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