Investigation of steroidogenesis mechanisms in prostate cancer progression: Effects of cytochrome P450 17A1 and steroid 5 alpha-reductase inhibitors

One in every eight Canadian men will be diagnosed with prostate cancer in their lifetime. Androgens, which are male sex hormones, are the primary driving force behind the development of prostate cancer and are synthesized in the testes, prostate, and in the prostate cancer tumour itself. Although once the standard of care, orchiectomy is rarely performed; continuous androgen deprivation is necessary when the cancer is very advanced. In these cases, the cancer becomes more aggressive and progresses to a stage called castration-resistant prostate cancer, which does not respond to hormonal agents. Dutasteride and abiraterone acetate are two current treatments for prostate cancer. The actions of these therapies are complementary, targeting different androgen metabolizing enzymes. Currently, dutasteride is successfully used for benign prostate hyperplasia, which is non-cancerous enlargement of the prostate. Abiraterone acetate, which was been approved in April 2011, is a promising treatment option for advanced prostate cancer patients. Clinical studies have shown that a subset of prostate cancer patients manifested resistance to abiraterone, and this suggests that there are compensatory mechanisms at work, either by supplying androgens via alternative biosynthetic pathways and/or by altering the signaling pathways involved in prostate cancer progression. The purpose of Dr. Subrata Deb’s research is to investigate the effects of abiraterone and dutasteride on pathways of androgen biosynthesis in castration-resistant prostate cancer. Mouse models of human prostate cancer, human prostate cancer cells, and human prostate tissues will be used to determine the effect of dutasteride and abiraterone acetate, either alone or in combination, on androgen formation during castration-resistant prostate cancer or in resistance to abiraterone. The aim of this research is to find the potential reasons for treatment failure in prostate cancer and aid in the development of potential treatment strategies.