Functional Characterization of eRNA-Coregulator Interactions at AR-Bound Enhancers in Advanced Therapy-Resistant Prostate Cancer
Abstract
In this project, I will address the PCRP Overarching Challenge of defining the biology of lethal prostate cancer to prevent death. Although men with prostate cancer initially respond well to existing therapy, tumors ultimately develop resistance and relapse to the lethal stage of the disease. Mechanisms that contribute to therapy resistance are poorly understood and need to be studied further to improve treatment outcomes. Prostate cancer is fueled by naturally occurring hormones called androgens – the best known is testosterone. In order for androgens to exert their effects – both in normal development and in prostate cancer – they require a receptor, which is present in many different organs of the body. When androgens are present, they cause the androgen receptor to binds to DNA sequences, called enhancers, to control the rate at which genes are expressed. In prostate cancer, binding of the androgen receptor to enhancers is altered, leading to changes in expression of genes that cause promote cancer growth and, we believe, in the later stages of disease can cause therapy resistance. It is this mechanism I propose to unpick in order to identify potential new treatments for this lethal stage. At enhancers, the androgen receptor interacts with a number of factors, including small DNA-like molecules, called enhancer RNA (eRNA), and accessory factors, called coregulators. While coregulators have long been known to act in concert with the androgen receptor to facilitate its activity, roles for eRNA remain largely unknown although recent evidence suggests they promote coregulator recruitment and functions. In this project, I will specifically focus on eRNA and determine whether changing their levels affects androgen receptor associated gene expression, cancer cell growth, and therapy resistance. Like other similar RNA molecules, eRNAs have potential as therapeutic targets. Although the aim of using them clinically to achieve improved clinical outcomes is some years off, my research will lay the groundwork for future targeting of eRNA by identifying the candidates that are likely to have the most effects on therapy resistance and ultimately has the potential to provide more therapeutic options for men at lethal stages of the disease. To provide robust evidence to support this, I will test these effects extensively in laboratory-based models of prostate cancer. My long-term goal is to establish a career in prostate cancer research and my principal interests lie in understanding mechanisms that enable tumors to become resistant to therapy in order to improve outcomes for men suffering from prostate cancer. This research will help me develop key expertise through training in state-of-the-art genomic and computational methods that are essential for my future career in prostate cancer research. I will be supported in achieving my goals by my mentors, Prof. Charlotte Bevan and Dr. Moray Campbell, and their laboratory teams, who have a track record of working together in transatlantic partnership.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210059
Entities
People
- Rayzel Fernandes
Organizations
- Imperial College London
- United States Army