5-1 reductase 2 inhibitors are commonly used for medical management of patients with obstructive uropathy secondary to benign prostatic hyperplasia (BPH). Finasteride, the most commonly used 5-1 reductase inhibitor, is prescribed to 8.2 million American men. Based on our preliminary results, we estimate that 2.37 million of those men are resistant to its therapeutic action, because they do not express its intended target enzyme, 5-1 reductase 2, accounting for $640 million in annual health care spending. Despite its common use, mechanisms accounting for resistance to Finasteride are not understood. To explore why some patients are resistant to the widely used 5-1 reductase type 2 inhibitor, we evaluated the degree of expression of 5-1 reductase 2 in human prostate tissues. We found that there is a wide variability of expression of 5-1 reductase 2 in human prostate samples with 30% of different samples lacking expression of the protein. Since methylation of the CpG dinucleotide islands in the promoter region of genes has been associated with regulation of genes, we investigated whether the 5-1 reductase gene contains CpG islands. We found that the 5-1 reductase 2 promoters contains a rich CpG island and in fact the CpG island is methylated in many prostate cell lines which do not express 5-1 reductase 2. In addition, there is a strong correlation between methylation of 5-1 reductase 2 promoter regions and absence of 5-1 reductase 2 in human prostate samples. Therefore, we hypothesize that methylation of the promoter region of 5-1 reductase 2 gene is associated with reduced expression of the protein, which can lead to stagnant or suppressed prostatic growth in adulthood, and possibly accounting for resistance to 5-1 reductase 2 inhibitor therapies. This clinical study is designed to explore the heterogeneous growth pattern of adult human prostates as related to expression of 5-1 reductase 2, and to evaluate the mechanisms of resistance to 5-1 reductase 2 inhibitions.
The specific aims are:
Specific Aim #1. To determine whether methylation of 5-1 reductase 2 promoter region is associated with repression of 5-1 reductase 2 protein in human prostate tissue.
Specific Aim #2. To determine whether methylation of 5-1 reductase 2 promoter is associated with decreased prostatic growth rates.
Specific Aim #3. To determine whether methylation of 5-1 reductase 2 promoter and reduced expression of 5-1 reductase 2 is associated with resistance to Finasteride in management of BPH. Our proposal is well-aligned with NIH/NIDDK's Prostate Research Strategic Plan. The findings will have broad implications for chronic use of 5-1 reductase 2 inhibitors for BPH, and also in newly suggested strategies for chemoprevention of prostate cancer. Recognition of mechanisms that regulate expression of 5-1 reductase 2 will lead to identification of newer compounds and better targeted therapies for BPH and reduce the rates of invasive therapies for this benign condition.
Inhibition of 5-1 reductase, the enzyme responsible for development and growth of prostate, is commonly utilized for treatment of patients suffering from lower urinary tract symptoms secondary to benign prostatic hyperplasia. However, 30% of human prostates do not express 5-1 reductase. Here we investigate mechanisms that may account for different prostate growth patterns and resistance to therapy in adult men.
|Preston, Mark A; Wilson, Kathryn M; Markt, Sarah C et al. (2014) 5?-Reductase inhibitors and risk of high-grade or lethal prostate cancer. JAMA Intern Med 174:1301-7|
|Bechis, Seth K; Otsetov, Alexander G; Ge, Rongbin et al. (2014) Personalized medicine for the management of benign prostatic hyperplasia. J Urol 192:16-23|