Loss of DHT Glucuronidation Enables Hormone Therapy Resistance
Abstract
Prostate cancer is the most frequently diagnosed non-skin cancer and the second leading cause of cancer-related death in men in the United States. Androgens are hormones that are also key factors controlling the initiation and progression of prostate cancer. When androgens bind to the androgen receptor (AR) in prostate tumor cells, this promotes tumor cell growth, which leads to tumor growth and disease progression. Androgen deprivation therapy (ADT) is the first-line treatment strategy for advanced prostate cancer. ADT is achieved by medical castration, which uses drugs to inhibit gonadal androgen synthesis and is often combined with other drugs to prevent the androgen receptor from binding androgens. Although ADT is effective initially, within 12 to 24 months after therapy most patients experience tumor recurrence. Recurrence usually evolves as a castration-resistant state that no longer responds to ADT; this state is referred to as castration-resistant prostate cancer (CRPC). It is well established that androgens play a major role in CRPC progression. Although CRPC can be treated with a newer androgen synthesis inhibitor or a stronger AR blocker, it soon becomes resistant to these treatments as well. Nearly all prostate cancer deaths result from this treatment-resistant state. Therefore, solving the problem of how castration resistance develops is essential to finding new treatments or even preventing CRPC. Dihydrotestosterone (DHT) is the most potent androgen present in prostate tissue. DHT can move into the cell to activate the AR, but it is rapidly inactivated by proteins known as UDP-glucuronosyltransferase (UGT) enzymes. By comparing castration-resistant and castration-sensitive prostate cancer cell lines, we found the UGT enzyme activity disappears in the CRPC cell line, but not in the castration-sensitive prostate cancer cell line. As a consequence, DHT is not inactivated in the CRPC cell line. Further, the genes for the UGT enzymes are lost in human prostate cancer samples. All these results suggest that androgen inactivation is a key factor in castration-resistant disease. I hypothesize that in patients with CRPC, UGT activity is lost and that this leads to an elevated DHT concentration in the tumor that promotes tumor growth. If proven true, this investigation will lay the foundation for future studies of the clinical significance of this loss of androgen inactivation and preclinical studies to test treatment for androgen inactivation loss, with the eventual goal of developing new clinical treatment strategies for CRPC. My professional goal is to become an independent researcher focusing on translational investigations of androgen metabolism in CRPC. I first began to work in the area of prostate cancer in graduate school, mentored by Dr. Charlie Chen, one of the key participants in demonstrating that CRPC requires androgen receptor and in developing the drug enzalutamide, which subsequently was approved to treat CRPC. After graduation, I joined Dr. Nima Sharifi s research team at the Cleveland Clinic, which includes both PhD scientists and urology and oncology trainees. Dr. Sharifi is a prostate cancer medical oncologist whose clinic is dedicated solely to treating patients with prostate cancer, most of whom have advanced CRPC. He identified the first mutation in the androgen-synthesizing machinery that increases androgen function in tumor cells and is responsible for CRPC. He also conducts clinical trials for experimental hormonal therapies. Therefore, his combination of clinical insight and extensive basic science knowledge of androgen metabolism is especially suited for guiding this project toward future clinical translation. We will meet at least twice a week to discuss experimental design, review results, and discuss future objectives. He will also ensure that I have opportunities to present my work at formal seminars at Cleveland Clinic, as well as at national conferences and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510487
Entities
People
- Ziqi Zhu
Organizations
- Cleveland Clinic
- United States Army