Targeting the Androgen Receptor Splice Variant 7 in Castration-Resistant Prostate Cancer
Abstract
Androgen deprivation therapy (ADT) remains the first-line treatment option for patients with advanced metastatic prostate cancer. Androgens stimulate prostate cancer cell growth and survival by binding to its receptor, the androgen receptor (AR). Androgen binds to the AR and activates its function, the activated AR is then able to bind DNA and turn on or off the transcription of its target genes. ADT inhibits the actions of androgens, either through binding the AR and inactivating it or limiting androgen production. However, despite initial responses to ADT, the majority of patients develop resistance to ADT and progress to castration-resistant prostate cancer (CRPC). Despite the continuous inhibition of androgens and the AR, CRPC cells continue to depend on AR signaling. It is thought that AR splice variants (shortened or truncated forms of AR) may be primarily responsible for the failure of ADT. The AR splice variant, ARv7, in particular, has been implicated in driving growth of CRPC cells. ARv7 is also associated with poorer patient prognosis and with resistance to ADT. ARv7 is continuously active and does not depend upon androgen for its activity, rendering it immune to the actions of ADT. Presently, it is not understood how ARv7 drives growth of CRPC or how it is regulated. In this proposal, we seek to better understand how ARv7 is regulated and which ARv7-regulated genes are responsible for driving CRPC growth. We will also test a novel therapy that has the potential to target ARv7 and decrease CRPC growth and survival. We hope that our study will illuminate a potential therapeutic strategy for targeting the ARv7, which has proven thus far to be difficult to inhibit. Additionally, our study will shed further light on how ARv7 drives growth and survival of CRPC and may suggest additional therapeutic targets that may be inhibited to decrease CRPC growth and survival. My ultimate career goal is to become an independent investigator studying AR dysfunction in prostate cancer. My mentor, Dr. Myles Brown, is a world-renowned scientist with expertise in steroid hormone receptor biology in breast and prostate cancers. Dr. Brown has successfully trained over 25 postdoctoral fellows who have gone on to have successful careers as independent investigators. I meet with Dr. Brown regularly and receive his feedback and insight into the project. Furthermore, I frequently attend weekly research seminars, departmental meetings, and monthly prostate cancer research meetings that allow me, not only to learn about new research, but also to connect and collaborate with other prostate cancer researchers at the Dana Farber Cancer Institute. I am passionate about finding solutions and improving patient outcomes, and I believe that the DOD Early Investigator Research Award in Prostate Cancer will facilitate the achievement of my long-term goals.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910296
Entities
People
- Irene Lee
Organizations
- Dana–Farber Cancer Institute
- United States Army