Targeting Prostate Cancer Lineage Plasticity with BET Bromodomain Inhibition

前列腺癌细胞的谱系可塑性--定义为雄激素受体(AR)信号和开关的缺失 从腔到交替分化程序-现在被认为是致命性的关键决定因素 前列腺癌。最致命的形式是神经内分泌前列腺癌(NEPC)。新的NEPC很少见 (1%的患者)。然而，我们最近发现，去势诱导的紧急治疗(t-nepc) 更常见于对阿比特龙或苯扎鲁胺等药物耐药的男性肿瘤中。这 强烈提示AR干扰促进了这一表型的出现。目前还没有有效的治疗方法 对于t-NEPC，由于t-NEPC的侵袭性，t-NEPC患者经常被排除在临床试验之外。因此， 显然有必要开发新的治疗方法。 最近，我们发现特异性转录因子(TF)和BET溴域蛋白BRD4 合作促进t-NEPC分化和细胞存活。此应用程序旨在澄清 这些转录因子和BRD4发挥作用的机制，并阻断这些机制。我们的长期目标是 制定防止出现致命性t-NEPC的药理策略。为了实现这一目标，我们 已确定使用BET抑制剂(Beti)或BET PROTAC降解剂靶向BET溴域蛋白 (BETD)是一种很有前景的方法，可以阻断向t-NEPC的谱系转换，并在体外阻断t-NEPC细胞的存活。 我们在这里描述的研究旨在测试BRD4和合作的TF激活的假设 维持t-NEPC细胞存活的谱系可塑性计划；以BRD4/TF轴为靶点是合理的 预防或延缓t-nepc疾病进展的方法。 目的1：确定BRD4与特定的转录因子协同促进基因表达的机制 T-nepc谱系可塑性生存计划。完成这一目标将提供对 BRD4和协同因子如何促进谱系可塑性，并将决定这些因子的激活 TFS是良好的BET抑制剂反应的可靠预测标志。 目的2：用Beti或BETd治疗t-NEPC小鼠移植瘤并检测其抗肿瘤活性 活性和NEPC分化。完成这一目标将为Beti或BETD临床提供理论基础 在t-nepc患者中进行试验，并确定适应性耐药机制。 目的3：使用Beti或BETd预防去势诱导的t-NEPC谱系转换 小鼠移植t-nepc血统开关模型。这一目标的完成将为测试提供理论基础 在t-NEPC转换的高危患者中应用Beti或BETd，并确定反应的生物标志物。 我们期望所提出的研究将机械地阐明转录网络的功能 对t-NEPC的出现和生存至关重要。这些结果将有助于确定阻止这一点的新方法 近期t-nepc男性患者的网络状况。

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.