Genetics may explain drug's role in prostate cancer prevention

Key Points

"Our findings begin to provide evidence for how 5-alpha-reductase inhibitors may prevent prostate cancer. We know clinically, from the results of the Prostate Cancer Prevention Trial (using finasteride), that prostate cancer incidence is decreased by this therapy, but the molecular pathways that this treatment alters with respect to the development of prostate cancer have not been worked out," Elahe Mostaghel, MD, PhD, a research associate at the Fred Hutchinson Cancer Research Center, University of Washington, Seattle, told attendees of the Prostate Cancer Symposium.

In anticipation of the outcome of the REDUCE trial, a large prostate cancer prevention trial examining the effect of dutasteride (Avodart), Dr. Mostaghel and colleagues conducted an exploratory study to examine the possible genetic mechanisms by which dutasteride may reduce prostate cancer risk. Results of the REDUCE trial are expected in 2 years.

Dr. Mostaghel's group looked for gene changes in 75 men with localized prostate cancer. Twenty-five had prostatectomy alone, 26 were given neoadjuvant dutasteride, 0.5 mg, and the remaining 24 received dutasteride, 3.5 mg orally per day for 4 months prior to prostatectomy.

The study found that men who received dutasteride before surgery experienced a decrease in the expression of 98 genes and an increase in the expression of 32 genes. Notable was the discovery that the expression of a particular gene, Trefoil Factor 3 (TTF3), was reduced 2.1 fold. The overexpression of this gene has been associated with the development of prostate and other cancers. Men in the dutasteride groups also showed a 3.8-fold increase in the expression of insulin-like growth factor binding protein 3 (IGFBP3), a tumor-suppressor gene whose expression is decreased in prostate cancer.

"The importance of this study is in trying to determine which patients are benefiting from the therapy and why," Dr. Mostaghel said. "In the Prostate Cancer Prevention Trial, some patients in the treatment arm developed prostate cancer, while some did not. We do not yet understand why, but it may have to do with how the molecular pathways related to cancer development are affected by the drug therapy in each patient.

"If we could tell, perhaps by interim biopsies, whether the pathways identified in our study are being beneficially altered in individual patients, we might be able to predict which patients will benefit most from this therapy and which patients might be candidates for alternative chemopreventive strategies."

"Dr. Mostaghel showed that, by evaluating gene expression levels before and after therapy, you can indeed show that, locally, the androgen receptor acts effectively," commented Jack Schalken, PhD, professor of experimental urology at Radboud University, Nijmegen Medical Center in the Netherlands. "So a number of very important genes that are associated with the androgen responsiveness are found to be modulated."

Roger Rittmaster, MD, a co-author on the study, is director of urology clinical development and medical affairs at GlaxoSmithKline.