Notch-mediated 5ARI resistance in human BPH

Notch 介导的人类 BPH 中的 5ARI 耐药性

基本信息

批准号：
10183238
负责人：
Douglas William Strand
金额：
$ 37.86万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-20 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183238
关键词：
3-Dimensional 5 Alpha-Reductase Inhibitor Adrenergic alpha-Antagonists Androgen Receptor Androgens Apoptosis Atrophic Benign Prostatic Hypertrophy Biological Assay Blinded Categories Cell Line Cell Proliferation Cells Chronic Classification Clinical Clinical Trials Conflict (Psychology)Custom Data Discrimination Drug resistance Epithelial Epithelial Cells Flow Cytometry Fresh Tissue Growth Health Heterogeneity Histopathology Human Hyperplasia Image Incidence Link Magnetic Resonance Imaging Mediating Medical Molds Molecular Morphology Mus Muscle Tension Muscle Tonus National Institute of Diabetes and Digestive and Kidney Diseases Nodule Operative Surgical Procedures Oxidoreductase Pathogenesis Pathologist Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Production Prostate Prostatectomy Radiology Specialty Recommendation Reporting Research Resistance Risk Running Signal Transduction Smooth Muscle Specimen Stanolone Steroids Strategic Planning Testing Tissues Transgenic Animals Transgenic Mice Translational Research Urologist alpha-adrenergic receptor base biobank cell type experimental analysis human tissue improved inhibitor/antagonist innovation insight lower urinary tract symptoms molecular phenotype mouse model notch protein novel novel strategies personalized medicine predicting response public health relevance radiologist response side effect standard care therapy resistant tool transcriptome sequencing transcriptomics

项目摘要

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.

概括 α肾上腺素能受体阻滞剂（α-阻滞剂）是放松肌肉紧张以改善肌肉紧张的一线疗法。对于有下尿路症状 (LUTS) 的患者排尿，但对较小的、非纤维化的患者最有效类固醇 5a-还原酶抑制剂 (5ARI) 阻止二氢睾酮 (DHT) 的局部产生，代表通过结合管腔上皮细胞凋亡来缩小前列腺体积的唯一疗法。这两种疗法都很昂贵，有不良副作用，并且无法完全降低症状风险这些数据表明我们尚未针对调节 BPH 的多种发病机制进展。了解 5ARI 耐药性的分子发病机制是该委员会的高度优先建议 NIDDK 前列腺研究战略计划。可变药物反应与药物反应之间的潜在联系。我们提出了一种创新的方法来解构组织病理学特征。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很大程度上是由于缺乏全面的转化研究通过将样本分类为组织病理学类别来解释异质性的人体组织研究。这里重点关注约 60% 患者中可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 正在发挥作用减少结节中的 DHT，但未能诱导管腔上皮细胞凋亡，表明 5ARI 耐药； 2) 5ARI 抗性结节的管腔上皮的 RNA-seq 显示 Notch 通路活性升高。管腔上皮 Notch 信号传导驱动人类 BPH 中 5ARI 耐药结节形成的假设三个关键证据：1) 5ARI 之前和之后将依次对患者进行 MRI 治疗以确定腺结节是否消退；2) 5ARI 耐药的结节手术标本将通过 LC-MS/MS 和组织病理学检查患者，以将 DHT 独立性与 Notch 相关联 3) 腺结节外植体和具有异位Notch激活的转基因动物将被治疗确定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 耐药性的分子和表型分类以及非侵入性的临床工具 5ARI 耐药腺结节患者的歧视。关联关于 BPH 患者 5ARI 治疗失败原因的新见解为确定治疗 BPH 的新方法带来了巨大希望治疗 BPH 的药物疗法。