Targeting Chromatin Remodeling Complexes to Inhibit Oncogenic Androgen Receptor Activity in Prostate Cancer
Abstract
Scientific Rationale, Objective, and Aims of the Application: Cancer cells are reliant on certain proteins, known as transcription factors, that bind to DNA and activate expression of growth and survival genes in a process called transcription – the conversion of the genetic code found in our DNA into RNA. One of the most important transcription factors in prostate cancer development and progression is the androgen receptor (AR), which mediates the physiological effects of androgens. AR continues to play an important role in the lethal stage of the disease known as metastatic castration-resistant prostate cancer (mCRPC), despite therapies to directly inhibit AR or production of androgens. In mCRPC, AR regulates an aberrant transcriptional program in concert with other collaborating transcription factors, often through binding of DNA elements known as neo-enhancers. DNA is normally tightly wound and compacted by proteins called histones, and the DNA and histone proteins are collectively referred to as chromatin. The binding of AR and other factors at neo-enhancers is dependent on both the physical and chemical states of the chromatin in order to loosen or remodel the compacted DNA. Therefore, impeding the physical accessibility of DNA binding sites could be a novel strategy to inhibit the growth of prostate cancer cells that are addicted to transcription factor oncogenes, such as AR. One of the major chromatin remodeling factors is the mSWI/SNF complex, and this complex has been reported to be required for AR activity, thus suggesting that it could be a therapeutic target for prostate cancer treatment. Indeed, our preliminary experiments find that a compound that depletes protein expression of mSWI/SNF components required for activity (SMARCA2 and SMARCA4) preferentially inhibits growth of prostate cancer cells that express AR. Moreover, this compound, AU15330, induces compaction of open neoenhancers bound by AR and leads to decreased gene expression of AR targets. It is additionally intriguing that AU15330 can synergize with an existing inhibitor of AR activity, enzalutamide, that many patients with mCRPC are resistant to or will develop resistance. We therefore hypothesize that SMARCA2 and SMARCA4 degraders, like AU15330, are promising therapeutic compounds with the potential to decrease AR accessibility at neoenhancers and represent a novel treatment strategy for patients with mCRPC. We will test this premise through three aims. In Aim 1, we will use a variety of techniques in cell culture systems to determine the mechanism of action of a SMARCA2 and SMARCA4 degrader in detail at the DNA and RNA level. Aim 2 will use mouse models of prostate cancer to directly test whether treatment of prostate cancer cells with AU15330 can inhibit tumor growth. Aim 2 will also identify biomarkers of response to SMARCA2 and SMARCA4 degrader treatment, genes that can predict whether a positive response to a therapy will occur. Aim 3 will analyze the efficacy of AU15330 in combination with enzalutamide and in models where enzalutamide no longer inhibits cell growth; this will allow us to understand whether AU15330 may be effective in patients who are enzalutamide-resistant. Combined, the objective of our proposal is to generate valuable preclinical data to guide future clinical trials with the SMARCA2 and SMARCA4 degrader AU15330 in mCRPC patients. Clinical Applicability of the Research: The proposed project will utilize cutting-edge technologies to test the role of chromatin remodeling factors in mCRPC cells and the potential clinical utilization of compounds targeting these factors. Completion of this project will deepen our knowledge of the function of chromatin remodeling factors in the biology of mCRPC and provide proof of principle that targeting of chromatin remodelers is a promising strategy to decrease AR signaling in mCRPC. Successful development and translation of SMARCA degraders could have significant
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110500
Entities
People
- Lanbo Xiao
Organizations
- United States Army
- University of Michigan