Radiation-treatment failure is a major source of morbidity and mortality for men with localized prostate cancer. Based on pre-clinical studies, several mechanisms for radiation resistance have been proposed. However, only limited data are available from human studies. Recently, the androgen receptor (AR) has been shown to increase prostate cancer cell resistance to a host of therapies. In preliminary studies, radiation induced AR protein expression and prostate-specific antigen (PSA) secretion. This response was dependent on p53, a molecule recently recognized to modulate AR expression. Importantly, radiation- mediated AR transactivation occurred in a ligand-independent fashion. Thus, conventional androgen suppression (AS) may not maximally inhibit AR during radiation. We hypothesize that AR activation mediates prostate cancer cell radiation-resistance. The long-range GOALS of this project are: i) To determine the role of AR activity in the radiation resistance of human prostate cancer, ii) To develop a platform for testing novel agents against the AR in patients undergoing radiation therapy, iii) To employ this platform to discover novel tissue and serum biomarkers that will be useful in improving radiation sensitivity of human prostate cancer. To accomplish these goals we propose to focus on three SPECIFIC AIMS: 1. Determine the effect of radiation on AR expression and function in clinical prostate cancer, and the effect of pharmacologic AS on AR-axis signaling. 2. Determine the association of radiation-mediated p53 activation with AR expression and function in clinical prostate cancer. 3. To test whether levels of PSA, androgens and IGF-1 in serum can be used as surrogate markers of the effect of radiation on prostate cancer cells. To study these effects, prostate biopsies will be performed prior to and following radiation. The effect of radiation on p53-AR signaling and the ability of AS to prevent AR activation will be determined by comparing p53 and AR expression in pre- and post-radiation samples. Serum samples will be taken during radiation to determine if local tissue responses can be predicted using serum-based assays for PSA and other markers. Relevence: These studies will assess if radiation induces AR expression and activity in clinical prostate cancer, as observed in pre-clinical models. These studies promise to identify a novel mechanism of prostate cancer radiation-resistance in humans, determine to what extent AS is able to overcome resistance, and examine whether serial PSA testing during therapy could be a real-time clinical marker for radiation responsiveness.
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