Androgen receptor pathway inhibition through targeting PARP-2 in castration-resistant prostate cancer

通过靶向 PARP-2 抑制去势抵抗性前列腺癌中的雄激素受体通路

基本信息

批准号：
10279470
负责人：
Li Jia
金额：
$ 40.95万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10279470
关键词：
Adenosine Diphosphate Ribose Androgen Receptor Androgens Attenuated Benign Biochemical Genetics Biology Bos taurus PARP protein Cancer Patient Castration Chromatin Clinical DNA Repair Gene Data Development Enhancers Enzymes Family Future Gene Expression Generations Genes Genetic Genetic Transcription Genome Goals Growth Lead Ligand Binding Ligands Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Messenger RNA Metastatic Prostate Cancer Modeling Molecular Mutate Mutation Oncogenes Oncogenic Pathway interactions Patients Pharmacology Play Poly(ADP-ribose) Polymerases Polymers Pre-Clinical Model Property Prostate Prostate Cancer therapy Proteins RNA Splicing Receptor Activation Receptor Inhibition Receptor Signaling Reporting Research Resistance Role Site Therapeutic Tissues Transcription Coactivator Variant Work Yang abiraterone androgen deprivation therapy androgen sensitive androgenic base castration resistant prostate cancer clinical application clinically relevant efficacy testing evidence base genetic approach genome sequencing inhibitor/antagonist new therapeutic target novel novel therapeutic intervention prostate cancer cell prostate cancer model recruit targeted treatment therapeutic target therapy resistant transcription factor tumor tumor growth

项目摘要

ABSTRACT Androgen receptor (AR) is ligand-activated transcription factor and a driver of prostate cancer (PCa). Understanding the molecular mechanisms of AR-mediated transcription is a key for the development of novel therapeutic strategies for both castration-sensitive prostate cancer (CSPC) and castration-resistant prostate cancer (CRPC). It is well-known that AR transcriptional activity is prominently dictated by the transcription activator FOXA1, which acts as a ‘pioneer’ factor opening the condensed chromatin and facilitating the recruitment of AR. Genome sequencing studies have revealed that FOXA1 is one of the most frequently mutated genes in primary PCa and even more common in metastatic CRPC. Aberrant FOXA1 function is implicated in PCa development and progression likely through its impact on AR signaling. Therefore, inhibition of AR through targeting FOXA1 is a promising therapeutic approach for CRPC. However, to date FOXA1 has been deemed undruggable. We recently reported that critical to the function of FOXA1 is its modulation by poly-(ADP-ribose) polymerase 2 (PARP-2), conventionally known as a DNA repair protein. Our studies have demonstrated that PARP-2 is a critical component in AR signaling through interacting with FOXA1 and facilitating AR recruitment to prostate-specific enhancers. Expression of PARP-2 is significantly elevated in primary PCa tumors compared to benign prostate tissues, and even higher in CRPC tumors. Selective targeting of PARP-2 by genetic or pharmacological means blocks PARP-2/FOXA1 interaction, which in turn attenuates AR-mediated gene expression and PCa growth. These results lead us to the hypothesis that PARP- 2 plays a central role in AR-mediated transcription through interacting with FOXA1. Therefore, PARP-2 Inhibition attenuates AR signaling through disrupting FOXA1 function, which provides an alternative therapeutic strategy for AR inhibition without involving AR ligand binding. The overall objective of this project is to determine the molecular mechanisms by which selective targeting of PARP-2 inhibits CRPC growth through disruption of FOXA1 function and define PARP-2 as an alternative therapeutic target for CRPC. To attain the overall objective, we propose two specific aims: Aim 1: Determine the molecular mechanisms by which targeting the PARP-2/FOXA1 interaction inhibits AR signaling. Aim 2: Determine to what extent selective targeting of PARP-2 inhibits CRPC tumor growth in preclinical models. The successful implementation of this project will greatly advance our understanding of multifaceted biology of PARP proteins and their evolving impact on cancer therapeutics. More specifically, the results from the proposed research are expected to provide a strong basis for future development and clinical application of selective PARP-2 inhibitors benefiting patients with incurable metastatic CRPC.

抽象的雄激素受体（AR）是配体激活的转录因子和前列腺癌（PCA）的驱动因素。了解AR介导的转录的分子机制是新型发展的关键 cast割敏感的前列腺癌（CSPC）和耐Custatration抗性前列腺的治疗策略癌症（CRPC）。众所周知，AR转录活性是由转录显着决定的激活剂FOXA1，它是打开冷凝染色质的“先驱”因素，并支持招募AR。基因组测序研究表明FOXA1是最频繁的原代PCA中的突变基因，甚至在转移性CRPC中更常见。异常FOXA1功能是在PCA开发和进展中实施的可能是通过其对AR信号传导的影响。因此，抑制通过靶向FOXA1的AR是CRPC的一种有希望的治疗方法。但是，迄今为止FOXA1有我们最近报告说，对FOXA1的功能至关重要是它的调制聚（ADP-核糖）聚合酶2（PARP-2），通常称为DNA修复蛋白。我们的研究有证明PARP-2是通过与FOXA1相互作用和促进AR招聘到前列腺特异性增强剂。 PARP-2的表达显着升高原发性PCA肿瘤与良性前列腺组织相比，在CRPC肿瘤中甚至更高。选择性通过遗传或药物手段对PARP-2的靶向2 parp-2/foxa1相互作用，这又减弱AR介导的基因表达和PCA生长。这些结果使我们提出了这样的假设 2通过与FOXA1相互作用，在AR介导的转录中起着核心作用。因此，PARP-2 抑制作用通过破坏FOXA1函数来减轻AR信号，这提供了替代方案 AR抑制的治疗策略，而无需涉及AR配体结合。该项目的总体目的是确定选择性靶向的分子机制 PARP-2的PARP-2通过破坏FOXA1功能抑制CRPC的生长，并将PARP-2定义为替代方案 CRPC的治疗靶标。为了实现总体目标，我们提出了两个具体目标：目标1：确定靶向PARP-2/FOXA1相互作用的分子机制抑制了AR信号传导。目标2：确定PARP-2的选择性靶向在多大程度上抑制临床前模型中CRPC肿瘤的生长。这该项目的成功实施将大大促进我们对多方面生物学的理解 PARP蛋白及其对癌症治疗的影响。更具体地说，来自预计拟议的研究将为未来的发展和临床应用提供强大的基础选择性PARP-2抑制剂使无法治愈的转移性CRPC患者受益。