Investigating the Molecular Mechanisms of Acquired Resistance to BET Bromodomain Inhibitors in Castration-Resistant Prostate Cancer
Abstract
Background: Prostate cancer is the most common non-cutaneous malignancy and second leading cause of cancer-related mortality in men of the Western world. It has been estimated that about 1 in 7 men will be diagnosed with prostate cancer during his lifetime. While effective surgical, radiation, and androgen ablation therapy exists for clinically localized prostate cancer, progression to metastatic castration-resistant prostate cancer (CRPC) remains essentially incurable. Despite the success of recently approved therapies targeting androgen receptor (AR) signaling, durable responses are limited due to acquired resistance. BET bromodomain-containing proteins are a class of epigenetic regulators known as "chromatin readers," which bind to acetylated lysines on histones, recruit chromatin modifying enzymes, and can function as co-activators or co-repressors of gene transcription depending on the context. Selective small molecule inhibitors that target the amino-terminal bromodomains of BET proteins (BETi) have been shown to exhibit anti-proliferative effects in a range of malignancies including CRPC. BETi blocks AR signaling and is shown to be more efficacious than enzalutamide in blocking CRPC growth in vitro and in vivo. Several BETi are already in clinical trials for hematological malignancies and solid tumors including CRPC. Objective and Rationale: The aims of this proposal are to elucidate the mechanisms of acquired resistance to BETi therapy in prostate cancer and discover genes/network of genes including epigenetic reprograming pathways that can be targeted in resistant cells. Early results from BETi clinical trials have been encouraging, with durable patient responses; however, lessons from other targeted cancer therapies such as enzalutamide and abiraterone suggest that acquired resistance will eventually limit responsiveness to BETi treatment in CRPC. This proposal will utilize cutting-edge next-generation sequencing (NGS) technologies based on genetic and epigenetic assays along with molecular and cell biology techniques to study the following aspect of BETi resistance in prostate cancer: (1) What are the basic molecular mechanisms of acquired resistance to BETi therapy in prostate cancer? (2) How does BETi resistance change the chromatin structure of the cells? (3) Does PARP1 have a role in increased AR activity in BETi-resistant cells? (4) What is the mechanism of increased PRC2 activity in BETi-resistant cells? (5) What is the mechanism by DDR pathway is affected in BETi-resistant cell? (6) Will combing anti-androgen or PARPi or EZH2i have a synergistic effect on BETi therapy? Clinical Applicability: The goal of this project is to understand the basic mechanisms of acquired resistance to BETi therapy and activation of parallel pathways that can be efficiently targeted to treat mCRPC. While the initial discoveries will be immediately useful to understand the biology of BETi resistance and to evaluate the therapeutic potential of drug combination, our ultimate goal is to transform the scientific findings into clinical application. With support from prominent scientists in the field of prostate cancer, we are hopeful that we will be quickly able to translate our scientific findings into clinical treatments and prognostic tools. In summary, our highly innovative proposal directly addresses the overarching challenge of Prostate Cancer Research Program focus areas, specifically, to understand the intrinsic and extrinsic mechanisms contributing to primary and acquired resistance to therapy. We anticipate that the findings from this study will have a significant impact on prostate cancer biology and disease management in the clinics. By providing the foundation for rationale combination therapy with BETi for CRPC, this study may result in a significant advancement towards the goal of curing CRPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710404
Entities
People
- Irfan Asangani
Organizations
- United States Army
- University of Pennsylvania