Developing Novel Synthetic Steroids as Multifunctional Probes in the Investigation of Steroid Metabolism in CRPC
Abstract
Scientific Objective: Advanced prostate cancer is the second leading cause of death for men in the United States. In 2019, the number of new prostate cancer cases is estimated at 174,650, with about 31,620 prostate cancer-related deaths—a 7% increase from 2018. The male steroid hormones, testosterone and 5a-dihydrotestosterone (DHT), activate the androgen receptor and cause prostate cancer cells to proliferate. Thus, progression of prostate cancer depends on androgen receptor activation. The standard first-line treatment for prostate cancer, androgen deprivation therapy (ADT) by medical or surgical castration, severely decreases testosterone, so androgen receptor activation also ceases. In many cases, despite the low testosterone level achieved with ADT, the cancer becomes resistant to this treatment, and castration-resistant prostate cancer (CRPC) develops. CRPC is the cause of nearly all prostate cancer deaths. However, it remains unclear where the testosterone and DHT come from or how the androgen receptor continues to be activated. Hence, solving the problem of treatment resistance and improving early diagnosis of cancer recurrence are the most important missions for prostate cancer researchers. Steroids labeled with radioactive fluorine (18F) for positron emission tomography (PET) imaging or biotin (a B vitamin) have several unique advantages that make them highly useful for evaluating the metabolic and molecular processes of prostate cancer. We believe that novel F-steroid probes can be used to predict the behavior and aggressiveness of prostate tumors by capturing specific aspects of steroid metabolism in CRPC; biotinylated steroids can be used to uncover associated proteins or genes involved in synthesis of testosterone or DHT. This knowledge will drive development of new therapies for resistant disease and improve personalized treatment. Therefore, I hypothesize that synthesized 18F-DHEA and biotinylated DHT and A5diol can be employed as novel chemical probes to investigate how steroids promote CRPC. In this project, I will design multiple ways to synthesize 18fluorine and biotinylated steroid probes, optimize each step of the syntheses, and then determine probe uptake or proteins associated with them in prostate tumor tissue to investigate the metabolic mechanism of prostate cancer in vitro and in vivo. Applicability: If my hypothesis is correct, this research project will capture new and specific pathways of steroid metabolism that are critical in CRPC. The results will provide entirely new insights into the biology and physiology of prostate cancer that will improve treatment for CRPC and potentially prostate cancer in general. Thus, this work will define the biology of lethal prostate cancer to reduce death and lead to treatments that improve outcomes for lethal prostate cancer. Career Goals: My professional goal is to lead an academic research laboratory that focuses on high-impact translational investigation of metabolic mechanisms and development of new treatments and biomarkers of prostate cancer through combining synthetic chemistry and cell/molecular biology. I completed my Ph.D. degree in synthetic chemistry in Dr. William D. Wulff’s laboratory at Michigan State University. Dr. Wulff is an organic chemist who is dedicated to developing new synthetic methodologies to make compounds with high efficiency and applying them in the total synthesis of various natural substances. After I graduated, I came to the Cleveland Clinic as a postdoctoral fellow in Dr. Nima Sharifi’s laboratory. Dr. Sharifi is a medical oncologist whose clinic is dedicated solely to treating patients with prostate cancer, most of whom have CRPC. He also conducts clinical trials of experimental hormonal therapies at the Cleveland Clinic and groundbreaking research in prostate cancer steroid metabolism to improve patient treatment. Being part of a team that includes both biochemists and clinical urology and o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110116
Entities
People
- Yijing Dai
Organizations
- Cleveland Clinic
- United States Army