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

摘要 雄激素受体（AR）是配体激活的转录因子，是前列腺癌（PCa）的驱动因子。 了解AR介导的转录的分子机制是开发新的 去势敏感性前列腺癌（CSPC）和去势抵抗性前列腺癌的治疗策略 癌症（CRPC）。众所周知，AR的转录活性主要由转录调控决定。 激活剂FOXA 1，它作为一个“先锋”因子打开浓缩的染色质，并促进 招募AR。基因组测序研究表明，FOXA 1是最常见的 在原发性PCa中存在突变基因，在转移性CRPC中甚至更常见。FOXA 1功能异常 可能通过其对AR信号传导的影响参与PCa的发展和进展。因此，抑制 通过靶向FOXA 1来治疗AR是CRPC的一种有前途的治疗方法。然而，迄今为止，FOXA 1 被认为是不可治愈的我们最近报道，FOXA 1的功能的关键是它的调制， 聚（ADP-核糖）聚合酶2（PARP-2），通常称为DNA修复蛋白。我们的研究 证明PARP-2是AR信号传导中的关键组分，通过与FOXA 1相互作用， 促进AR募集到前列腺特异性增强子。PARP-2的表达显著升高， 与良性前列腺组织相比，原发性PCa肿瘤中，CRPC肿瘤中甚至更高。选择性 通过遗传或药理学手段靶向PARP-2阻断PARP-2/FOXA 1相互作用， 减弱AR介导的基因表达和PCa生长。这些结果导致我们假设PARP- 2通过与FOXA 1相互作用在AR介导的转录中起着重要作用。PARP-2 抑制通过破坏FOXA 1功能减弱AR信号传导，这提供了一种替代方法。 用于AR抑制而不涉及AR配体结合的治疗策略。 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FOXA 1功能抑制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，我们提出了两个具体目标：目标1：确定 靶向PARP-2/FOXA 1相互作用抑制AR信号传导的分子机制。目标二： 确定在临床前模型中选择性靶向PARP-2抑制CRPC肿瘤生长的程度。的 该项目的成功实施将极大地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， 建议的研究有望为未来的开发和临床应用提供强有力的基础， 选择性PARP-2抑制剂使无法治愈的转移性CRPC患者受益。

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.