BPTF-Mediated Gene Regulation in Prostate Cancer
Abstract
Prostate cancer is one of the most common cancers in men, and metastatic disease causes death of most prostate cancer patients. The androgen receptor (AR) is a protein that plays a key role in regulating growth and survival of prostate cancer cells. Thus, therapy targeting and inactivating the AR is currently the primary treatment for metastatic prostate cancer. Despite initial regression of prostate cancer after AR-targeted therapy, prostate cancer always recurs and progresses to a lethal stage called castration-resistant prostate cancer (CRPC), largely because AR activity is reactivated by various cellular mechanisms. New-generation AR inhibitors are now the primary treatment for CRPC, but the benefit of such treatment remains limited as CPRC develops resistance to even those drugs. Therefore, it is critical to understand biochemical mechanisms driving CRPC progression in order to identify new therapeutic targets. AR functions in a complex with several other proteins, and thus AR activity can be disrupted indirectly by targeting those AR-associated proteins. In this application, we identified a protein that regulates gene expression called BPTF as one such AR-associated protein that, when targeted, inhibits AR activity. BPTF levels are high in CRPC tissues, and BPTF inhibition antagonizes CRPC tumor growth. We have defined a novel mechanism whereby BPTF interacts with AR to enhance its activity, and BPTF inhibitors can be used to target AR-BPTF interaction. Based on these preliminary findings, we will test the main hypothesis that BPTF promotes AR activity, and BPTF inhibitors can be used as potential CRPC therapy. We will test this hypothesis in four experimental aims. Aim 1 will use biochemical approaches to determine how BPTF enhances AR activity on the molecular level. Aim 2 will use state-of-the art genomics approaches to assess whether high levels of BPTF in prostate cancer cells increase AR activity. In Aim 3, we will genetically deplete or overexpress BPTF and then monitor CPRC growth in cell culture systems or in mouse prostate cancer models. We will conduct similar experiments using BPTF inhibitors. Aim 4 will analyze a large, already-assembled collection of human prostate cancer tissues and determine whether high BPTF levels correlate with AR activity, prostate cancer progression and shorter patient survival times. In the short term, we hope to better understand how BPTF promotes AR activity and confers resistance to AR-targeted therapy. If we are successful, BPTF expression in tumors could be monitored as a marker of aggressive prostate cancer and even targeted by novel therapies. In the long term, we hope to encourage interest in developing more potent BPTF inhibitors for patients with CRPC. Finally, this project addresses two of the PCRP Overarching Challenges: Define the biology of lethal prostate cancer to reduce death and Develop treatments that improve outcomes for men with lethal prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210363
Entities
People
- Jianfei Qi
Organizations
- United States Army
- University of Maryland, Baltimore