AR Proxisomes: Exploring Loci-Specific Role of AR and Its Coregulators in Castration Resistance
Abstract
Androgen deprivation therapy (ADT) is a cornerstone of treatment for advanced prostate cancer. However, after an initial dramatic response, the therapy invariably fails as cancer cells become resistant to therapy and the disease progresses to a castration-resistant stage. It is unclear how this resistance is acquired; however, studies indicate that the androgen receptor that is targeted by ADT regains activity and androgen receptor signaling continues unabated driving cancer progression. Androgen receptor functions as a transcription factor that binds to certain defined DNA sequences and affects expression of its target genes that drive tumor proliferation and invasion. The androgen receptor is aided by various chromatin regulatory proteins that help the receptor in executing its cancer-promoting function. Understanding the nature and identity of these chromatin co-regulators is essential, as it will not only provide insights into how prostate cancer becomes castration-resistant, but also help in targeting these regulators with drugs to prevent castration-resistance. Traditional approaches to study the role of chromatin regulator proteins in castration resistance are often non-physiological and rely on a limited number of reagents(antibodies) raised against known chromatin regulators. These approaches do not offer insights about novel chromatin regulators that may play a role in castration resistance. We intend to fill this gap by devising a strategy that is physiologically relevant, highly precise, and can identify novel chromatin regulators and the downstream genes that they regulate. This strategy would provide a high-resolution map of how chromatin co-regulatory protein cooperates with androgen receptor to bring about castration resistance, a feat that has never been achieved before. The first aim in our proposal will devise a labeling strategy to identify known and unknown chromatin coregulators that drive castration resistance, and the second aim will utilize the strategy in human prostate cancer organoids, which are prostate tumors that can be grown in laboratory culture conditions. These studies will identify novel chromatin regulators and provide physiological relevant information about how AR aided by chromatin regulators drives castration resistance. We hope to provide an unprecedented map of how castration resistance is driven at a molecular level, offering novel molecular targets for overcoming castration resistance. We envisage that this endeavor will expand our knowledge about chromatin co-regulators of androgen signaling and provide novel targets for castration-resistant prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310098
Entities
People
- Sushant K. Kachhap
Organizations
- Johns Hopkins University
- United States Army