Aberrant Tumor Metabolism Enables GR Takeover in Enzalutamide-Resistant Prostate Cancer
Abstract
Prostate cancer (PCa) 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 key factors, controlling the initiation and progression of PCa. When androgens bind to the androgen receptor in prostate tumor cells, they promote tumor growth and disease progression. Androgen deprivation therapy (ADT) is the first-line treatment strategy for advanced PCa. ADT is usually achieved by medical castration, which uses drugs to inhibit gonadal androgen synthesis. 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 condition is called castration-resistant PCa (CRPC). Androgens remain crucial for CRPC progression. Therefore, the advent of new drugs that target the androgen receptor, such as enzalutamide (ENZ), has been beneficial for many patients with CRPC. Unfortunately, although this new drug has proven effective in clinical practice, resistance still develops, typically within months. Nearly all PCa deaths occur because resistance develops to currently available therapies. Therefore, solving the problem of treatment resistance is crucial to finding effective treatments for CRPC. It has been recently established that increased levels of a different hormone receptor, the glucocorticoid receptor (GR), confers resistance to ENZ in CRPC. In the human, cortisol is the main activator of the GR, and intracellular cortisol concentration is controlled by two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD): 11beta-HSD1 and 11beta-HSD2. Our preliminary findings in LAPC4 cells indicate that long-term treatment with ENZ decreases 11beta-HSD2 protein expression but has no effect on 11beta-HSD1, which slows cortisol inactivation and intensifies GR stimulation. Our further preliminary studies show that increasing the 11beta-HSD2 level not only accelerates basal cortisol inactivation, but also reverses the ENZ-induced metabolic features and reverses ENZ resistance in animal models of PCa tumors. Moreover, another molecule, autocrine mobility factor receptor (AMFR), plays a critical role in ENZ-mediated regulation of 11beta-HSD2. These findings suggest that AMFR is a potential target for reversing ENZ resistance in CRPC. I hypothesize that 11beta-HSD2 activity is decreased in patients with ENZ resistance, leading to elevated cortisol concentrations that promote tumor growth via GR signaling. If proven true, this investigation will lay the foundation for future studies of the clinical significance of cortisol inactivation and preclinical studies to test whether reinstating 11beta-HSD2 expression has therapeutic effects, with the eventual goal of developing new clinical treatment strategies for ENZ-resistant CRPC. My professional goal is to lead an academic research laboratory that focuses on high-impact translational investigations of drug resistance in PCa. During my PhD research, I studied the enzyme 11beta-HSD2. This experience gave me expertise in glucocorticoid metabolism, which is essential for the research I propose here. After receiving my Ph.D., I joined Dr. Nima Sharifi s research team at the Cleveland Clinic, which includes both PhD scientists as well as clinical urology and oncology trainees. Dr. Sharifi is a PCa medical oncologist whose clinic is dedicated solely to treating patients with PCa, most of whom have advanced CRPC. He also conducts clinical trials for experimental hormonal therapies. Recently, Dr. Sharifi identified a novel abiraterone metabolite, delta4-abiraterone, which is present in patients with CRPC treated with abiraterone acetate and has more potent anti-tumor activity than abiraterone itself. Therefore, his combination of clinical insight and extensive basic science knowledge of androgen metabolism will be of enormous benefit in th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610270
Entities
People
- Jianneng Li
Organizations
- Cleveland Clinic
- United States Army