Investigating mechanisms that drive castrate-resistant prostate cancer

The last in a series of lab notes from our awardees, discussing their own research.

Daniel Tamae, Ph.D. - Postdoctoral Assoc., University of Pennsylvania

Prostate cancer is the most frequently diagnosed form of cancer and the second leading cause of cancer death in males in the developed world. Great advances have been made in the early diagnosis and treatment of prostate cancer. However, there is ample room to improve the clinical outcome for individuals diagnosed with the most aggressive form of the disease. Prostate cancer is an androgen driven disease, so the vast majority of therapies have been specifically designed to deprive the tumor of androgens. Historically, this was accomplished by surgical castration and removal of the adrenal glands. Today, we have several drugs that essentially accomplish the same effect. However, even with the most advanced drugs, a subset of patients will develop castrate-resistant prostate cancer (CRPC), which renders all treatments ineffective and the patient ultimately succumbs to the disease.

Our lab has been at the forefront in studying one of the key enzymes in androgen biosynthesis, an enzyme known as AKR1C3. The expression of this enzyme tracks with prostate cancer progression and has been found to be consistently higher in prostate tumors during androgen deprivation therapy and in CRPC patient tumors. My project utilizes a technology known as triple quadrupole mass spectrometry, which is the gold standard for quantifying small molecules such as androgens. I have developed a strategy for quantifying 11 key androgen metabolites that are of interest to us in driving tumor growth. The method has since been applied to two high profile clinical trials which enrolled high-risk prostate cancer patients in order to test the efficacy of new drug combinations and one of the newest drugs to hit the prostate cancer space, respectively. The quantitative androgen data from the patient serum before, during and after drug treatment gave us some really interesting insights into patient response to therapy and potential routes for the development of CRPC. Based on the clinical data, we hypothesize that the prostate tumor adapts to castrate conditions during drug treatment by elevating AKR1C3 levels within the tumor. This allows the tumor to convert adrenal androgens that do not normally bind to the androgen receptor (AR) and to manufacture its own active androgens that will drive AR-mediated tumor growth and metastases.

We are now applying these insights from our mass spectrometry data in concert with our body of knowledge on the enzymes involved in androgen biosynthesis in order to tease out mechanisms of CRPC and develop new drug targets to inhibit AKR1C3 and to improve survival for patients battling CRPC.