Inhibiting Lysine-Specific Demethylase 1 Activity as a Potential Therapeutic Treatment for Castration-Resistant Prostate Cancer
Abstract
Androgen, one type of male hormone, is not only important for normal prostate development but also critical for prostate cancer development. Androgen exerts its function through binding to its receptor protein, androgen receptor (called AR), which can subsequently bind to the regulatory sites of certain genes in chromatin and regulate their expression in prostate cancer cells. Patients with metastatic prostate cancer can be treated with androgen deprivation therapies to block AR function. However, the tumors will eventually develop resistance in a more aggressive stage of cancer (termed castration-resistant prostate cancer [CRPC]), and AR function is restored. Recently, more aggressive androgen deprivation therapies were introduced using two Food and Drug Administration-approved drugs (abiraterone/Zytiga and enzalutamide/Xtandi) to treat CRPC. The majority of CRPC patients respond initially to these treatments, but most relapse by 1 year. AR activity is once again restored in at least a subset of patients. One mechanism contributing to the resistance is increased expression of certain AR splice variants, particularly AR-V7 (a truncated form of AR that cannot be bound by androgens but is constitutively active). Therefore, there is a pressing need to develop new treatment strategies to target the activities of androgen receptor and its splice variants. Our published and unpublished studies suggest that a chromatin-associated protein LSD1 (Lysine Specific Demethylase 1) plays a major role in regulating AR activity in prostate cancer cells. LSD1 is an important enzyme that catalyzes a modification process on histone proteins, and it may have novel functions in regulating AR. In particular, our data suggest that LSD1 can directly modify FOXA1, a pioneer factor that is required for AR binding to the regulatory sites of genes. We showed that LSD1 inhibition can disrupt FOXA1 pioneer factor function and thus impair the subsequent binding of AR or AR-V7. The impairment of AR-V7 chromatin binding and function is particularly important, as AR-V7 activity is generally resistant to the enzalutamide treatment. Moreover, we showed in animal studies that LSD1 inhibition can suppress tumor growth in an AR-V7-driven CRPC model and can further act in synergy with enzalutamide treatment. In this project, we will try to understand the mechanisms of actions of LSD1 on maintaining FOXA1 activity and subsequent chromatin binding of AR and AR splice variants and further assess the efficacy of LSD1 inhibitor in patient-derived xenograft mouse models. Based on the findings of these studies, we may further test LSD1 inhibitor treatment in combination with those androgen deprivation agents in preclinical models of CRPC. If these studies support LSD1 as a therapeutic target in CRPC, our subsequent objective would be to develop phase 1 clinical trials in a well-defined subset of CRPC patients, with robust translational endpoints based on findings in this study.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910361
Entities
People
- Changmeng Cai
Organizations
- United States Army
- University of Massachusetts Boston