Defining Transcription Factor Networks Governing Androgen Receptor-Null Prostate Cancer
Abstract
Background: About 29,000 American men die each year from prostate cancer (PCa), whose growth is driven by the androgen receptor (AR), a transcription factor (TF) protein that in turn regulates global gene expression essential for prostate biology. AR inhibitors are used for advanced PCa, but tumor relapse is universal usually due to reactivation of AR activity. Since the approval of potent, current AR-targeting drugs, it has been recognized that cancers can escape therapy by substantially reducing AR expression. This AR-low/null state is particularly worrisome as there are no drugs designed to target these tumors. Rationale: There remains interest in developing even more potent AR inhibitors (AR degrader drugs). In order to anticipate potential mechanisms of resistance to these new therapies, in preliminary data we ve modeled the consequences of maximum AR inhibition by using genetic tools to deplete AR in PCa cells. Remarkably, there was a rapid outgrowth of these AR-null cells that formed tumors in mice. Gene expression analysis showed that, despite the absence of AR, some genes regulated by AR were still partially expressed, likely through compensation by alternative TFs. These findings demonstrate that, even if a "perfect" AR drug becomes available, PCa cells can likely maintain a subset of gene expression activity formerly controlled by AR. Objective and Ultimate Applicability of the Research: There is an unmet need to gain a thorough understanding of the mechanisms that allow PCa to evolve to an AR-low/null state; the objective of this Idea Development Award. Completion of the proposed studies will identify novel genetic functions critical to the survival of PCa cells with acquired resistance to intensive AR-targeted therapies. The work will lay a foundation for the future development of molecularly targeted agents beyond that of AR inhibitors. PCRP Overarching Challenge Classification: Define the biology of lethal prostate cancer to reduce death. Specific Aims: Aim 1. Determine gene expression and regulatory changes occurring in response to potent AR inhibition. Our preliminary data showed different levels of growth inhibition seen from current AR drugs vs. anti-AR genetic tools. We will utilize genomic tools over a series of time points to uncover global patterns of gene regulation and expression down to single-cell resolution and correlate these findings with growth responses. This will enable identification of rare subsets of cells primed to resist attack or highlight a prevalent emergency response pathway to overcome powerful AR inhibitors. Aim 2. Identify vulnerabilities responsible for maintenance of the AR-low/null state. Preliminary gene expression data obtained from AR-null tumors highlighted the possible increased activity of specific TFs that may compensate for lack of AR. Other candidate TFs are also likely to emerge from Aim 1. Here, we will seek to functionally determine whether these TF genes are vital to the survival of the AR-low/null state. We will augment these efforts with an unbiased growth assessment (screen) of all genes to identify candidates (irrespective of their biological function) that are specifically critical for AR-null PCa. Aim 3. Characterize the AR-low/null state in patient tumor samples. An ongoing, funded MSK protocol is prospectively imaging patients with molecular agents that provide assessment of AR expression status. We will use that study as a source of patient tumor biopsies, which will yield both AR-positive and AR-low/null samples. We will utilize the same single cell gene expression technologies (as in Aim 1) to visualize gene expression networks active in advanced patient tumors, generating a unique dataset with unprecedented detail. Additionally, we will grow tumor cells obtained from these patient biopsies in the laboratory, establishing new model systems of AR-low/null disease identified as such while in the patient. These
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010289
Entities
People
- Charles Sawyers
Organizations
- Sloan-Kettering Institute
- United States Army