Androgen signaling in BPH: Lower Urinary Tract Symptoms (LUTS) affects about 30% of men aged 50 and over and is generally considered a sign of clinically significant benign prostatic hyperplasia (BPH). Androgens and aging are two known important factors in BPH pathogenesis. In addition, other factors, such as inflammation, are also implicated in BPH development. Deviation of androgen responsiveness is thought to be a key step in BPH initiation. However, the molecular nature of such a deviation remains unclear. Recently we investigated the expression of 4 androgen-responsive genes in human BPH specimens and found that the composite androgen-response index, which reflects the expression of multiple androgen-responsive genes, is increased ~4-fold in BPH relative to the adjacent normal cells. Our objective is to explore mechanisms leading to the elevated androgen signaling in BPH. The hypothesis is that aging, inflammation, and/or increased 5a- reductase II activity can enhance androgen signaling in BPH.
Two specific aims are proposed to test the above hypothesis. 1. Determine the alterations of androgen signaling in BPH and aging human prostate. BPH specimens and donor prostate tissues are available. The androgen signaling will be assessed by determining the expression of androgen-responsive genes by laser capture microdissection (LCM) coupled with real-time PCR and immunohistochemistry. 2. Conduct a Phase II Clinical Trial to test the hypothesis that celecoxib, a non-steroid anti- inflammatory drug (NSAID), and/or finasteride, a 5a-reductase II inhibitor, can inhibit the elevated expression of androgen-responsive genes in BPH tissues in patients. A four-arm, phase II randomized, single-blind clinical trial will be conducted in men with BPH, who are naove to androgen manipulation and chronic NSAID exposure. After randomization, men will be exposed to the study drugs celecoxib and finasteride alone or in combination or to no treatment (and strict avoidance of NSAIDs and 5a-reductase inhibitors) for 4 weeks. All of the specimens collected will be coded and blinded to investigators who will perform molecular and histological analysis. The basic, translational and clinical studies in this application will provide insights into the abnormally elevated androgen signaling in BPH, which may lead to new prevention and/or treatment of the disease.
The project will investigate the roles of aging, inflammation, and 5a-reductase II in elevated expression of androgen-responsive genes in benign prostatic hyperplasia (BPH). Elucidating the mechanism(s) of abnormal androgen signaling elevation in BPH may lead to new approaches for BPH prevention and/or treatment.
|Funahashi, Yasuhito; O'Malley, Katherine J; Kawamorita, Naoki et al. (2014) Upregulation of androgen-responsive genes and transforming growth factor-?1 cascade genes in a rat model of non-bacterial prostatic inflammation. Prostate 74:337-45|
|O'Malley, Katherine J; Eisermann, Kurtis; Pascal, Laura E et al. (2014) Proteomic analysis of patient tissue reveals PSA protein in the stroma of benign prostatic hyperplasia. Prostate 74:892-900|