Clarifying Mechanisms of BET Bromodomain Inhibitor Response in Castration-Resistant Prostate Cancer
Abstract
One American man dies every 16 minutes from metastatic castration-resistant prostate cancers (CRPCs) that are resistant to all therapies, including new drugs that block the androgen receptor. Recent work, including studies from our laboratory, has identified a novel, important molecular target in CRPC cells -- BET bromodomain proteins. Developing a new treatment strategy for CRPC patients targeting BET bromodomain proteins is the focus of this application. Several pharmaceutical companies have developed drugs to block the function of these proteins. These so-called BET bromodomain inhibitors are currently in clinical testing in blood cancers, but there is little understanding of how BET bromodomain inhibitors may help treat men with prostate cancer. We have observed that BET bromodomain proteins cooperate with other DNA-binding proteins to turn on important cancer-associated genes in CRPC cells. However, several critical questions must be answered before these therapies can be tested in clinical trials in men with CRPC: What are the key DNA binding proteins whose function is blocked by BET bromodomain inhibitors in CRPC? How do CRPC tumors resist treatment with BET bromodomain inhibitors? Are there specific gene or cellular changes in CRPC cells that indicate response to BET bromodomain inhibitors? Finally, are there specific groups of CRPC patients who are most likely to benefit from treatment with BET bromodomain inhibitors? This proposal is designed to answer all of these questions. One way to understand how cancer cells function is by studying models of cancer in the laboratory setting. A cancer cell line model is developed by taking a tumor biopsy from a patient and growing it in a Petri dish in the laboratory. This approach is appealing because the cell line model can then be studied in many ways, for instance, to understand how it responds to therapy. The result of these studies can then be used to inform and understand observations made in the clinic. In supporting studies, we treated our collection of CRPC cell lines with a BET bromodomain inhibitor called JQ1 and measured the gene expression changes. This enabled us to identify a gene signature of response (i.e., gene changes that occurred in all the cell lines that were responsive to this drug). Moreover, our analysis identified several proteins that may be responsible for JQ1 s effectiveness. Consequently, Aim 1 will confirm the importance of these proteins by inactivating them in prostate cancer cell lines and determining if this leads to similar effects as BET bromodomain inhibitor treatment. Doing so will help us determine how JQ1 kills cancer cells and will allow us to devise therapeutic strategies to enhance the effectiveness of BET bromodomain inhibitors. Our analytical approach identified proteins that may contribute to resistance to BET bromodomain inhibitor treatment. Importantly, specific drugs are known to block the function of several of these resistance-associated proteins. Accordingly, Aim 2 will test combinations of these drugs with BET bromodomain inhibitors. This will lead to more effective combinations of drugs that make BET bromodomain inhibitor treatment work even better. Our final goal is to identify biomarkers that signify that BET bromodomain inhibitors have hit their molecular target and that the "hit" is predictive of a therapeutic effect in a given CRPC cell. We have begun to use a new microscopy system to identify important changes in cancer cell appearance that contribute to the anti-tumor activity of BET bromodomain inhibitors. Consequently, Aim 3 will build on these results and identify additional, important changes in cancer cell appearance. Further, Aim 3 will determine if there are specific subsets of CRPC patient tumors that have high expression of genes from our BET bromodomain inhibitor gene signature. This will enable us to identify specific groups of CRPC patients who may benefit from BET br
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610601
Entities
People
- Laura M Heiser
Organizations
- Oregon Health & Science University
- United States Army