Targeting Lysine-Specific Demethylase 1 to Prevent Androgen Receptor Reactivation in 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) and regulate gene expression in the cells. One major function of these androgen-regulated genes is to drive differentiation of normal prostate. Patients with metastatic prostate cancer can be treated with standard androgen deprivation therapies including surgical or medical castration in order to block androgen receptor function. However, the tumors will eventually develop resistance in a more aggressive stage of cancer (termed castration-resistant prostate cancer, CRPC) and androgen receptor function is restored and also reprogrammed to favor expression of genes regulating proliferation instead of differentiation. Recently, more aggressive androgen deprivation therapies were introduced using two newly Food and Drug Administration-approved drugs (Zytiga and Xtandi) to treat CRPC. The majority of CRPC patients respond initially to these treatments, but most relapse by 1 year through unclear mechanisms. AR activity is once again restored in at least a subset of patients. The failure of this more aggressive androgen deprivation treatment indicates the need for new treatment strategies to target androgen receptor functions. Our recent studies suggest that a nuclear protein LSD1 (Lysine Specific Demethylase 1) plays a major role in regulating androgen receptor 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 androgen receptor. In particular, our data suggest that increased LSD1 activity may be a driver for reprogramming androgen receptor function, and thus targeting LSD1 may provide a novel approach to treat CRPC. In this project, we will try to understand the mechanisms of actions of inhibiting LSD1 in prostate cancer preclinical 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
- Jan 31, 2017
- Source ID
- W81XWH1610445
Entities
People
- Changmeng Cai
Organizations
- United States Army
- University of Massachusetts Boston