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)的驱动力。 了解AR介导的转录的分子机制是开发新药的关键 去势敏感型前列腺癌(CSPC)和去势抵抗型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决定 激活剂FOXA1，其作用是打开浓缩的染色质并促进 应收账款招聘。基因组测序研究表明，FOXA1是最常见的 基因突变在原发性前列腺癌中更为常见，在转移性前列腺癌中更为常见。异常FOXA1函数是 可能通过对AR信号的影响而参与前列腺癌的发生和发展。因此，抑制 靶向FOXA1的AR是治疗CRPC的一种有前景的治疗方法。然而，到目前为止，FOXA1已经 被认为是无法下药的。我们最近报道，FOXA1功能的关键是它通过 多聚(ADP-核糖)聚合酶2(PARP-2)，通常被称为DNA修复蛋白。我们的研究已经 通过与FOXA1和FOXA1的相互作用证明了PARP-2是AR信号中的关键组件 促进AR招募到前列腺特异性增强剂。PARP-2的表达显著升高。 原发性前列腺癌与良性前列腺组织相比，在CRPC肿瘤中甚至更高。有选择性的 通过遗传或药物手段靶向PARP-2可阻断PARP-2/FOXA1相互作用，进而 抑制AR介导的基因表达和前列腺癌生长。这些结果使我们得出假设，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 抑制通过干扰FOXA1功能来减弱AR信号，这提供了另一种选择 不涉及AR配体结合的AR抑制的治疗策略。 这个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功能抑制CRPC生长，并将PARP-2定义为替代 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/FOXA1相互作用抑制AR信号的分子机制。目标2： 在临床前模型中确定选择性靶向PARP-2在多大程度上抑制CRPC肿瘤的生长。这个 该项目的成功实施将极大地促进我们对生物多样性的理解 PARP蛋白及其对癌症治疗的演变影响。更具体地说，来自 所提出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.