Tuesday, June 17, 2025
6/17/2025
Targeting Prostate Cancer Lineage Plasticity with BET Bromodomain Inhibition - Lineage plasticity in prostate cancer cells—defined as loss of androgen receptor (AR) signaling and switch from a luminal to an alternate differentiation program—is now recognized as a critical determinant of lethality in prostate cancer. The most virulent form is neuroendocrine prostate cancer (NEPC). De novo NEPC is rare (<1% of patients). However, we recently found that castration-induced, treatment-emergent (t-NEPC) is much more frequently found in tumors from men resistant to drugs such as abiraterone or enzalutamide. This strongly suggests AR interference promotes the emergence of this phenotype. There are no effective therapies for t-NEPC, and t-NEPC patients are often excluded from clinical trials due to t-NEPC’s aggressiveness. Thus, there is a clear need to develop new treatments. Recently, we discovered that specific transcription factors (TFs) and the BET bromodomain protein BRD4 cooperate to promote t-NEPC differentiation and cell survival. This application is designed to clarify mechanisms by which these TF and BRD4 function and to block those mechanisms. Our long term goal is to develop pharmacological strategies that prevent the emergence of lethal t-NEPC. Towards that goal, we determined that targeting BET bromodomain proteins with BET inhibitors (BETi) or BET PROTAC degraders (BETd) is a promising approach to block the lineage switch to t-NEPC and to block t-NEPC cell survival in vitro. The studies we describe herein are designed to test the hypotheses that BRD4 and cooperating TFs activate a lineage plasticity program that sustains survival of t-NEPC cells; targeting this BRD4/TF axis is a rational approach to prevent or delay t-NEPC disease progression. Aim 1: Determine mechanisms by which BRD4 cooperates with specific TFs to promote expression of a t-NEPC lineage plasticity survival program. Completion of this aim will provide a detailed understanding of how BRD4 and cooperating factors promote lineage plasticity and will determine whether activation of these TFs is reliable predictive marker of favorable BET inhibitor response. Aim 2: Treat t-NEPC patient tumors implanted in mice with BETi or BETd and measure anti-tumor activity and NEPC differentiation. Completion of this aim will provide the rationale for BETi or BETd clinical trials in t-NEPC patients and identify adaptive resistance mechanisms. Aim 3: Prevent castration-induced t-NEPC lineage switch with BETi or BETd using a patient tumor model of t-NEPC lineage switch implanted in mice. Completion of this aim will provide the rationale to test BETi or BETd in patients at high-risk for t-NEPC conversion and identify biomarkers of response. We expect that the studies proposed will clarify mechanistically the function of transcriptional network that is critical for the emergence and survival of t-NEPC. These results will help identify new approches to block this network in men with t-NEPC in the near-term.
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