UT Southwestern PCF Young Investigator Identifies New Pathway Explaining Resistance to Prostate Cancer Treatment
Discovery Opens Door to New Target for Drug Development
July 29, 2011 -- One of the most vexing problems for clinicians treating prostate cancer patients is the inevitable onset of patient resistance to treatment with antiandrogens (androgen deprivation therapy or ADT) such as Lupron or Zoladex. Resistance is also seen in some patients being treated with new drugs such as Zytiga (abiraterone) that prevent a patient’s body from synthesizing testosterone and dihydrotestosterone (DHT), the fuel for prostate cancer. Zytiga is prescribed for patients after treatments with ADT and chemotherapy have failed.
With ADT, a patient’s normal hormone system is suppressed, 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.
To date, researchers widely believed that androgen synthesis and patients’ 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.
The recently FDA-approved drug, Zytiga, has proven successful in blocking the CYP17A pathway and prolonging the lives of patients who have been treated with nearly all conventional therapies.Yet, some patients still develop resistance to Zytiga.
A PCF-supported Young Investigator (2008), Nima Sharifi, MD, at UT Southwestern Medical Center in Texas, has discovered a second 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 that prostate cancer cells can create DHT without testosterone—long thought to be the “starting block” for DHT synthesis—was counter-intuitive to scientists. Until now. This finding is not only first-in-class, it might also guide drug discovery for Zytiga- and ADT-resistant patients.
"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 discovery and validation of this new DHT-synthesis pathway provide potentially druggable targets for new therapeutics for patients resistant to ADT and CYP17A-inhibiting drugs such as Zytiga. This latest discovery by a PCF Young Investigator provides hope that the problem of treatment resistance in prostate cancer patients will be solved and that advanced metastatic prostate cancer can be conquered.