Notch-mediated 5ARI resistance in human BPH

总结 α肾上腺素能受体阻滞剂（α-受体阻滞剂）是缓解肌肉紧张的一线治疗， 下尿路症状（LUTS）患者的排尿，但对较小的非纤维化患者最有效 前列腺类固醇5 α-还原酶抑制剂（5ARI）阻断双氢睾酮（DHT）的局部产生， 代表了通过腔上皮细胞凋亡缩小前列腺体积的唯一疗法。结合 这两种疗法都是昂贵的，具有不希望的副作用，并且不能完全减缓症状的风险。 进展这些数据表明，我们还没有针对调节BPH的各种病因 进展 了解5ARI耐药的分子发病机制是一个高优先级的建议， NIDDK前列腺研究战略计划。可变药物反应与 组织病理学特征研究甚少。我们提出了一种创新的方法来解构 一种流行的5ARI耐药表型的分子发病机制：腺结节。 关于BPH发病机制的相互矛盾的数据主要是由于缺乏全面的翻译， 人体组织研究，通过将样本分组到组织病理学类别中来解释异质性。我们 在这里，我们重点关注在约60%的患者中观察到的腺结节表型，并证明两个关键点 在我们的初步数据中：1）患者雄激素和5ARI水平的LC-MS/MS显示5ARI起作用 减少结节中的DHT，但未能诱导管腔上皮细胞凋亡，表明5ARI抗性;和 2)来自5ARI抗性结节的腔上皮的RNA-seq显示出升高的Notch途径活性。我们将测试 假设腔上皮Notch信号传导驱动人BPH中5ARI抗性结节形成， 三个关键证据：1）MRI将在5ARI之前和之后对患者依次进行 治疗，以确定是否腺体结节消退; 2）结节手术标本从5ARI耐药 将通过LC-MS/MS和组织病理学检查患者，以将DHT独立性与Notch 活性;和3）腺结节外植体和具有异位Notch激活的转基因动物将被处理以 确定Notch抑制是否使前列腺对5ARI治疗敏感。成功完成我们的目标 将建立5ARI耐药的分子和表型分类以及非侵入性的临床工具， 鉴别患有5ARI耐药腺结节的患者。 相关性 对BPH患者如何失败5ARI治疗的新见解为确定新的治疗方法提供了很大的希望。 前列腺增生症的治疗方法

Summary Alpha adrenergic receptor blockers (α-blockers) are a first line therapy for relaxing muscle tension to improve voiding in patients with lower urinary tract symptoms (LUTS), but are most effective on smaller, non-fibrotic prostates. Steroid 5a-reductase inhibitors (5ARI) block the local production of dihydrotestosterone (DHT), representing the only therapy for shrinking prostate volume through apoptosis of luminal epithelia. Combining both of these therapies is expensive, has unwanted side effects, and fails to fully slow the risk of symptomatic progression. These data suggest that we have yet to target the variety of pathogeneses regulating BPH progression. Understanding the molecular pathogenesis of 5ARI resistance is a High-Priority Recommendation of the NIDDK Strategic Plan for Prostate Research. The potential links between variable drug response and histopathological features are poorly studied. We present an innovative approach to deconstructing the molecular pathogenesis of a prevalent 5ARI resistant phenotype: the glandular nodule. The conflicting data on the pathogenesis of BPH is largely due to a lack of comprehensive translational human tissue studies that account for heterogeneity by binning specimens into histopathological categories. We focus here on a glandular nodule phenotype observable in ~60% of our patients and demonstrate two key points in our preliminary data: 1) LC-MS/MS of androgen and 5ARI levels in patients revealed that 5ARIs are functioning to reduce DHT in nodules, but are failing to induce luminal epithelial apoptosis, suggesting 5ARI resistance; and 2) RNA-seq of luminal epithelia from 5ARI resistant nodules shows elevated Notch pathway activity. We will test the hypothesis that luminal epithelial Notch signaling drives 5ARI-resistant nodule formation in human BPH with three critical pieces of evidence: 1) MRI will be sequentially performed on patients before and after 5ARI treatment to identify whether glandular nodules regress; 2) nodular surgical specimens from 5ARI-resistant patients will be examined by LC-MS/MS and histopathology for correlating DHT independence with Notch activity; and 3) glandular nodule explants and transgenic animals with ectopic Notch activation will be treated to determine whether Notch inhibition sensitizes the prostate to 5ARI treatment. Successful completion of our aims will establish a molecular and phenotypic classification of 5ARI-resistance and a clinical tool for non-invasive discrimination of patients with 5ARI-resistant glandular nodules. Relevance New insight into how BPH patients fail 5ARI therapy holds great promise for identifying novel approaches to medical therapy in the treatment of BPH.