The objective of the program project is to develop a novel mechanism-driven strategy for prostate cancerprevention. The approach is based on suppressing androgen signal transduction at two different stepssimultaneously by using finasteride to inhibit the formation of dihydrotestosterone and selenium to reduceandrogen receptor (AR) expression. The program is built along a bench-to-bedside paradigm and consistsof three highly integrated projects. Project 1 is to delineate how finasteride and selenium work cooperativelyto modulate certain molecular events in controlling the clonal expansion of prostate cancer cells. Specialemphasis is placed on the functional analysis of key targets and pathways responsible for the induction ofapoptosis following treatment with finasteride/selenium. Microenvironmental hypoxia is frequently seen in acolony of proliferating cancer cells due to abnormalities of the vasculature. It is well known that hypoxiaproduces a variety of molecular changes as a selective pressure for survival. There is recent evidencesuggesting that hypoxia facilitates AR activation and the transcription of androgen-responsive genes. Theabove process is mediated by a redox-regulating protein called peroxiredoxin-1, or Prx1. Prx1 ispreferentially elevated in prostatic intraepithelial neoplasia and prostate cancer cells. Project 2 is toinvestigate the mechanism of hypoxia/Prxl stimulation of AR signaling and to assess the role of Prx1 inmodifying the cancer control efficacy of finasteride/selenium. The findings of Projects 1 and 2 are critical tothe interpretation of the clinical trial results of Project 3. A short-term intervention trial is proposed to verifythe effect of finasteride/selenium on androgen target gene expression and apoptosis induction in prostatetissue samples obtained from pre-prostatectomy patients. A second objective of the trial is to determinewhether 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 willdie of this disease. As a public health problem, prostate cancer engenders huge medical care and humansuffering costs. Blocking the progression of small volume, low-grade neoplasia is increasingly beingrecognized as an important aspect of prostate cancer control. Our goal is to find a way of managing thedisease at an early stage in order to prevent it from becoming clinical relevant.
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