We al are very familiar with the significant problem in the treatment of prostate cancer, even therapies that initially work stop working and our disease continues to progress. The inevitable onset of this resistance to treatment with antiandrogens (ADT) such as Lupron or Zoladex is not limited just to this class of drugs. We have seen that even in the newly approved drug Zytiga (abiraterone) is subject to this resistance problem. Similarly, resistance also develops in some men being treated with the 5ar-inhibitors that prevent a man’s body from synthesizing testosterone and dihydrotestosterone (DHT), the fuel for prostate cancer.
ADT is designed to tamp down prostate cancer by blocking the production of testosterone and causing tumor cells to die. As a result, levels of PSA (prostate-specific antigen) are lowered. However, when starved of normal testosterone levels, the body is able to compensate by synthesizing testosterone and DHT (androgens) through alternate mechanisms.
It has been believed that androgen synthesis and the resulting resistance to treatment was accomplished in one process (pathway) in which a hormonal steroid—androstenedione (AD)—is created through a biosynthetic process using an enzyme known as CYP17A. AD would then create testosterone and the testosterone would subsequently create DHT. DHT is a powerful testosterone metabolite with two extra hydrogen atoms. Known by many men as the fuel for male pattern baldness, DHT is 10 times more powerful than testosterone for driving the growth, invasion and survival of advanced prostate cancer.
In a Prostate Cancer Foundation supported research project Nima Sharifi, MD, at UT Southwestern Medical Center in Texas, has discovered a second, alternative biosynthetic pathway. This new pathway supports the synthesis of DHT, but goes around testosterone. In some patients, Zytiga may be a “leaky drug” allowing some AD to continue being produced. In this pathway, the “leaked” AD binds with the enzyme SRD5A1 to create DHT. Dr. Sharifi’s discovery shows that prostate cancer cells can create their own DHT without testosterone.
“Our findings will change the framework for the way people think about this disease,” says Dr. Sharifi. “The general assumption is that the tumor accelerates through testosterone when, in fact, the pathway goes around it to the most potent hormone. We both found the existence of this pathway in models and patients, and have shown that these resistant tumors are clearly driven by this other pathway.”
The real excitement is that this discovery and validation of this new DHT-synthesis pathway will provide potential targets for new therapeutics for men resistant to ADT and CYP17A-inhibiting drugs such as Zytiga.
Joel T. Nowak, M.A., M.S.W.