4 Birds 1 Stone to Inhibit 5androstane-3alpha,17beta-diol Conversion to DHT
Abstract
Prostate cancer growth and recurrence relies on the relationship between the androgen receptor (the lock) and androgens (the key). The strong testicular androgens, testosterone and dihydrotesterone (DHT), activate the androgen receptor. Most, if not all, men who present with advanced prostate cancer are treated with androgen deprivation therapy. However, androgen deprivation therapy is not curative; prostate cancer recurs and causes death. One reason for prostate cancer recurrence is that tumors still make DHT during androgen deprivation therapy. Our laboratory studies the primary backdoor metabolism pathway. The last step in the primary backdoor pathway involves the conversion of androstanediol, an adrenal androgen metabolite, to DHT. This conversion is mediated by one of four enzymes. Protein sequence analysis showed that these four enzymes have a common site for activity. The goal of the proposed studies is to identify an inhibitor that blocks the activity of these four enzymes that convert androstanediol to DHT. Currently, no clinically useful inhibitors have been identified that can be used to block these enzymes. Blocking this step should reduce DHT levels further and tumors should regress. My career goal as a postdoctoral fellow under the guidance of James L. Mohler, MD is to further develop critical skills required to become an independent investigator conducting clinically relevant research in prostate cancer. Dr. Mohler designed a training plan that involves development of my understanding of prostate cancer treatment and recurrence and androgen metabolism. I have worked with faculty from multiple scientific disciplines to learn new and critical skills, such as mass spectrometry, fluorescence imaging, flow cytometry, and genomics. The training plan includes urology clinical and research journal clubs, genitourinary seminars, weekly project presentations, speaking at national and international conferences, improving my publication record, and acquiring career development grants. The goal of the research plan is to facilitate my transition from basic to translational science. This transition is guided by projects with clinically relevant outcomes, such as identifying an inhibitor to block androstanediol to DHT conversion. I have developed new techniques using prostate cancer cell lines, mouse models, and clinical tissues that complement my basic science areas of expertise. Completion of the research plan will provide publications required to acquire funding and opportunities to grow as a postdoctoral fellow. The award will help me transition from postdoctoral fellow to an assistant professor, tenure track position. The research plan involves mouse studies; I serve as the project manager and have learned all aspects of human prostate cell implantation for study of androgen metabolism. While my current publication record is small, the experiments outlined in my proposal are novel and will provide an excellent opportunity to establish a competitive publication record. The proposed studies have two clinically relevant outcomes that will advance the prostate cancer field. First, a high-throughput androgen metabolism inhibitor screen will be developed. Second, an inhibitor against the four enzymes that convert androstanediol to DHT will be discovered. The enzyme inhibitor will be used to enhance existing androgen deprivation therapy to cause tumor regression and extend survival of men with advanced prostate cancer. The fluorophore-based study could be modified to screen for inhibitors of other parts of the androgen metabolism pathways. Expanding the inhibitor screen will provide more opportunities to reveal inhibitors that lead to complete inhibition of androgen metabolism. Until the inhibitors are discovered and fully characterized, the research poses no known risks. The timeline for developing this project into clinical use is approximately 3 years once an inhibition has proven useful in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510409
Entities
People
- Michael V Fiandalo
Organizations
- United States Army