Role of AR-Derived Circular RNA in Prostate Cancer
Abstract
Prostate cancer is the most common non-cutaneous malignancy in men. Patients with localized prostate cancer can be effectively treated with local therapies (e.g., prostatectomy, radiation therapy); however, patients presenting evidence of disseminated disease will require treatment with systemic therapies that almost always involve targeting of the androgen receptor (AR) axis. Disease progression following AR-targeting therapies and the emergence of castration-resistant prostate cancer (CRPC) may be accompanied by molecular alterations of AR itself, including AR gene amplification, mutation, and AR variants, as well as key factors in AR regulation and ligand (androgens) synthesis. In addition, alterations in the epigenome and aberrant expression and function of microRNA (miRNA) and long non-coding RNA (lncRNA) are also implicated in CRPC. In this proposal, we will investigate a novel type of non-coding RNA named circular RNA (circRNA) that has recently been implicated in prostate cancer by focusing on unanswered but clinically relevant questions. Due to the diversity of circRNAs and critical role of the AR in prostate cancer, the main objective of the study is to characterize AR circRNA in CRPC. We will test the hypothesis that circARs act as competitive endogenous RNAs through sponging miRNA or RNA-binding proteins. To achieve this objective, we will thoroughly profile circARs in CRPC specimens (Aim 1), explore their functions relevant to CRPC biology (Aim 2), and determine their regulatory mechanisms during CRPC progression (Aim 3). The proposed studies were rich in technical details, but designed to generate new knowledge relevant to CRPC that can be utilized to drive target discovery in the emerging field of circular RNA focusing on the androgen receptor. Given the relevance of androgen receptor to CRPC detection and treatment and the general stability of circRNA that may be amenable to non-invasive detection, our proposed research may uncover important candidates for liquid-based detection targets that may be further tested in the therapeutic setting as predictive markers. Therefore, the current proposal addresses the FY19 PCRP Overarching Challenge, “develop treatments that improve outcomes for men with lethal prostate cancer.” Proposed research will also lead to an improved understanding of circRNA and may help to establish clinical relevance in the setting of CRPC. Therefore, the current proposal also addresses FY19 PCRP Overarching Challenge, “define the biology of lethal prostate cancer to reduce death.”
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010338
Entities
People
- Changxue Lu
Organizations
- Johns Hopkins University
- United States Army