Research Project
10247716
PROJECT SUMMARY/ABSTRACT Treatment options for patients with castration-resistant prostate cancer (CRPC) are expanding. However, 27,000 men will still die from this disease in 2017. We and others have found that widespread use of novel and more potent androgen receptor (AR)-targeting agents has increased the clinical frequency of virulent and untreatable AR-independent CRPC subsets. These subsets include: AR-indifferent prostate cancer (AIPC) with persistent AR expression but reduced AR function, neuroendocrine prostate cancer (NEPC), and AR-null tumors without neuroendocrine differentiation that we have termed double-negative prostate cancer (DNPC). However, very little is known about what factors promote the transition to and maintenance of specific AR-independent subsets. Furthermore, there are no effective treatments for patients with these tumors. The goal of this proposal is to overcome those deficits. Our studies using human AIPC, NEPC, and DNPC patient tumors and model systems identified specific transcriptional regulators, including BET bromodomain chromatin reader proteins, Master Regulator transcription factors (TFs), and kinases that are activated in AIPC, NEPC, and DNPC. In this proposal, we will test the overarching hypothesis that gene networks regulated by BET bromodomain proteins, aberrantly activated TFs or kinases, and other key signaling pathways promote AR-independent CRPC cell survival. We propose the following Aims: Aim 1: Determine the anti-tumor activity of the BET bromodomain inhibitor ZEN-3694 in patients with AR- independent CRPC. Aim 2: Identify and target critical Master Regulator transcription factors and kinases that promote AR- independent cell survival. Aim 3: Identify molecular markers of transition from AR-active to AR-independent CRPC subsets and identify and target critical pathways that promote survival of specific AR-independent subsets. The completion of the proposed work will lead to the development of rational clinical trials of BETi drug combinations to block critical networks that sustain the survival of AR-independent, lethal prostate cancers.
