Abiraterone Steroidal Metabolites as Biomarkers for Treatment Resistance in Prostate Cancer
Abstract
Scientific Objective: Advanced prostate cancer (PCa) is the third most common cause of cancer-related death among American men. In 2017, in the United States, the number of new PCa cases was estimated to be 160,000, with about 26,000 PCa-related deaths. Tumor progression depends on continued androgen receptor activity. Androgen receptor activation depends on two steroidal hormones, testosterone and dihydrotestosterone, which act as fuel for malignant cell growth. First-line treatment for advanced PCa is androgen deprivation therapy (ADT), either by surgical or medical castration, which deprives the cancer cells of their fuel. In many cases, despite the low serum testosterone level achieved with ADT, the cancer becomes resistant to treatment, and castration-resistant prostate cancer (CRPC) develops, which is the cause of nearly all PCa deaths. In CRPC, one of the mechanisms of treatment resistance is that the tumor cells become capable of producing their own androgens. Abiraterone blocks a key enzyme in androgen synthesis; patients treated with abiraterone have improved outcomes, as evidenced clinically by an increase in overall survival. However, resistance to abiraterone, as well as other treatments, develops eventually, and patients die from their disease. Therefore, solving the problem of treatment resistance is crucial to finding effective treatments for CRPC. It has been recently established that treating patients with abiraterone as a first-line treatment in combination with ADT increases overall survival, and this combination is now established as the new standard of care. We have reported that, in humans, abiraterone is metabolized by steroidogenic enzymes to at least seven steroidal compounds. Further, in vitro and in vivo, these abiraterone metabolites exert opposing effects with respect to prostate cancer progression. These findings suggest that abiraterone metabolism generates compounds that prevent CRPC progression, as well as others that can cause treatment resistance in CRPC. Therefore, I hypothesize that abiraterone steroidal metabolites play a crucial role in the development of treatment resistance in CRPC and can serve as biomarkers that will predict resistance to abiraterone treatment in patients with metastatic castration-sensitive prostate cancer. Applicability: If my hypothesis is correct, this investigation will lay the foundation for deciding the route of treatment for CRPC patients, providing a way to discriminate those who may benefit from abiraterone treatment from those with abiraterone-resistant disease. Receiving the most appropriate treatment as early as possible in the disease will prolong patients lives and improve their quality of life. Career Goals: My professional goal is to lead an academic research laboratory that focuses on high-impact translational investigations of drug resistance in PCa. I completed my Ph.D. work in the laboratory of Dr. Nima Sharifi at the Cleveland Clinic. Dr. Sharifi is a medical oncologist whose clinic is dedicated solely to treating patients with PCa, most of whom have advanced CRPC. He also conducts clinical trials of experimental hormonal therapies at the Cleveland Clinic. Being part of a team that includes both Ph.D. scientists and clinical urology and oncology trainees allows me to share my knowledge and gain significant insights into the clinical aspects of PCa and clinical research. As part of my Ph.D., I studied the metabolism of two steroidal compounds used as therapeutic agents in CRPC, abiraterone and galeterone. Both share the same chemical structure and, after developing a method to separate the metabolites, I found that abiraterone and galeterone were metabolized similarly by steroidogenic enzymes. This work gave me essential expertise in steroidogenic metabolism, which is crucial for the research I propose here. The Sharifi team, including myself, then used the separation method to identify seven novel metabolites o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810195
Entities
People
- Mohammad Alyamani
Organizations
- Cleveland Clinic
- United States Army