权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10430248
负责人：
Li Jia
金额：
$ 40.13万
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/10430248
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 enzalutamide evidence base genetic approach genome sequencing inhibitor 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，也是前列腺癌 (PCa) 的驱动因素。了解 AR 介导的转录的分子机制是开发新型药物的关键去势敏感型前列腺癌（CSPC）和去势抵抗性前列腺癌的治疗策略癌症（CRPC）。众所周知，AR转录活性主要由转录决定激活剂 FOXA1，作为打开浓缩染色质并促进染色质的“先锋”因子 AR的招募。基因组测序研究表明 FOXA1 是最常见的基因之一突变基因在原发性 PCa 中更常见，在转移性 CRPC 中更常见。 FOXA1 功能异常是可能通过其对 AR 信号传导的影响而参与 PCa 的发生和进展。因此，抑制通过靶向 FOXA1 来治疗 AR 是一种有前景的 CRPC 治疗方法。然而，迄今为止，FOXA1 已被认为是不可成药的。我们最近报道，FOXA1 功能的关键在于它的调节聚（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 通过与 FOXA1 相互作用而成为 AR 信号传导的关键组成部分促进AR募集到前列腺特异性增强子。 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，甚至在 CRPC 肿瘤中更高。选择性通过遗传或药理学手段靶向 PARP-2 可阻断 PARP-2/FOXA1 相互作用，从而反过来减弱 AR 介导的基因表达和 PCa 生长。这些结果使我们得出这样的假设：PARP- 2 通过与 FOXA1 相互作用在 AR 介导的转录中发挥核心作用。因此，PARP-2 抑制作用通过破坏 FOXA1 功能来减弱 AR 信号传导，这提供了一种替代方案不涉及 AR 配体结合的 AR 抑制治疗策略。该项目的总体目标是确定选择性靶向的分子机制 PARP-2 通过破坏 FOXA1 功能来抑制 CRPC 生长，并将 PARP-2 定义为替代方案 CRPC 的治疗靶点。为了实现总体目标，我们提出两个具体目标：目标 1：确定靶向 PARP-2/FOXA1 相互作用抑制 AR 信号传导的分子机制。目标 2：确定 PARP-2 的选择性靶向在临床前模型中抑制 CRPC 肿瘤生长的程度。这该项目的成功实施将极大地增进我们对多方面生物学的理解 PARP 蛋白及其对癌症治疗的不断变化的影响。更具体地说，结果来自预计该研究将为未来的开发和临床应用提供坚实的基础选择性 PARP-2 抑制剂使无法治愈的转移性 CRPC 患者受益。