Targeting Prostate Cancer Lineage Plasticity with BET Bromodomain Inhibition

通过 BET Bromodomain 抑制来靶向前列腺癌谱系可塑性

基本信息

批准号：
10220910
负责人：
Joshi James Alumkal
金额：
$ 37.24万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10220910
关键词：
ATAC-seq Androgen Receptor Bromodomain Cancer Patient Castration Cell Survival ChIP-seq Chromatin Clinical Trials Dependence Disease Progression Drug resistance E2F transcription factors Gene Expression Genes Genetic Transcription Goals Histology Histone Acetylation Histone H3 Implant In Vitro Lead Lysine Malignant neoplasm of prostate Measures Modeling Mus Neuroendocrine Prostate Cancer Nucleic Acid Regulatory Sequences Organoids Patients Pharmacology Phenotype Program Sustainability Prostate Prostate Adenocarcinoma Proteins Reader Receptor Signaling Sampling Signal Pathway Systems Biology Testing Time Transcriptional Activation Virulent Xenograft procedure abiraterone activating transcription factor design effective therapy high risk histone acetyltransferase inhibitor/antagonist loss of function men outcome prediction phase I trial predictive marker prevent programs prostate cancer cell prostate cancer cell line receptor function resistance mechanism response response biomarker transcription factor transcriptome sequencing treatment strategy tumor tumor growth

项目摘要

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.

前列腺癌细胞中的谱系可塑性 - 定义为雄激素受体（AR）信号的丧失和开关从腔到替代区分程序 - 被认为是杀伤性的关键决定因素前列腺癌。（<1％的患者）。从耐药到阿比罗酮或恩扎拉胺等药物的肿瘤中更常见强烈建议AR干扰促进这种表型的出现。因此，由于T-NEPC的侵略性，T-NEPC和T-NEPC患者通常被排除在临床试验之外。显然需要开发新的治疗方法。最近，我们发现特定的转录因子（TFS）和BET溴结构域BRD4 合作促进T-NEPC区分和细胞存活。这些TF和BRD4功能并阻止这些机制的机制。制定劳尔T-NEPC的出现的药理学策略。确定靶向用βbit蛋白（BETI）或BET Protac降解器靶向BET BET BET （BETD）是一种阻止谱系到T-NEPC并在体外阻断T-NEPC细胞存活的有前途的方法。我们设计的研究旨在测试BRD4和合作TFS激活的假设一种谱系塑料程序，该程序可以使T-NEPC细胞存活预防或延迟T-NEPC疾病进展的方法。目标1：确定BRD4与特定TF合作以促进表达的机制 T-NEPC血统塑料生存计划。 BRD4和合作因素如何促进谱系塑料，并将确定将激活这些因素 TFS是有利的BET抑制剂反应的可靠预测标记。 AIM 2：治疗植入Beti或Betd的小鼠中的T-NEPC患者肿瘤并测量抗肿瘤活动和NEPC差异性。 T-NEPC患者的试验并确定适应性抗性机制。 AIM 3：使用患者肿瘤通过BETI或BETD防止casttration诱导的T-NEPC谱系植入小鼠的T-NEPC谱系开关的模型。在高危患者中进行T-NEPC转化的患者的BETI或BETD并识别反应的生物标志物。我们预计提出的研究将阐明机械性转录网络的功能。对于T-NEPC的出现和生存至关重要。在近trm中患有T-NEPC的男性的网络。