ORLANDODutasteride, a 5-alpha-reductase (SRD5A) inhibitor currently used to treat benign prostatic hyperplasia (BPH), produces genetic changes in normal prostate tissue that may be protective against the development of prostate cancer, Elahe Mostaghel, MD, PhD, of the Fred Hutchinson Cancer Research Center, Seattle, reported at the 2007 ASCO Prostate Cancer Symposium (abstract 1).
The Prostate Cancer Prevention Trial found that SRD5A type 2 inhibition reduced the overall incidence of prostate cancer by 25%. This prompted Dr. Mostaghel and her coinvestigators to attempt to identify molecular changes underlying the chemopreventive or tumor-promoting effects of SRD5A inhibition.
The researchers obtained samples of noncancerous prostate tissue from 75 men diagnosed with localized prostate cancer who were randomly assigned to prostatectomy alone (25 patients) or to neoadjuvant dutasteride at 0.5 mg (26 patients) or 3.5 mg (24 patients) orally per day for 4 months prior to surgery. The men who received dutasteride before surgery experienced a decrease in the expression of 98 genes and an increase in the expression of 32 genes.
Dutasteride reduced the expression of trefoil factor 3 (TFF3), a gene linked to the development of prostate and other cancers, by more than 2.1-fold. At the same time, dutasteride increased by 3.8-fold the expression of insulin-like growth factor binding protein 3 (IGFBP3), a tumor-suppressor gene that is decreased in prostate cancer. Another important gene expression change was a decrease in transmembrane protease serine 2 (TMPRSS2). This gene is thought to promote growth of prostate tumors by fusing with ETS family oncogenes. TMPRSS2-ETS gene fusions have been found in 50% to 70% of prostate cancers, Dr. Mostaghel said.
Furthermore, dutasteride therapy resulted in a more than 90% decrease in serum dihydrotestosterone (DHT) levels in both the 0.5 mg and 3.5 mg groups. "We think decreasing DHT levels is important, because androgens may be involved in driving cancer development in the prostate," she commented.
The findings provide molecular support for the hypothesis that SRD5A inhibition in the prostate can beneficially impact prostate cancer development, Dr. Mostaghel said. However, she cautioned that her study has limitations, including a relatively short treatment period. "Our findings need to be evaluated in larger studies of longer duration," she said. "We are eagerly awaiting the results of the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which will be completed in 2009."