Notch-mediated 5ARI resistance in human BPH

Notch 介导的人类 BPH 中的 5ARI 耐药性

• 批准号: 10413136
• 负责人: Douglas William Strand
• 金额: $ 37.35万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-20 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413136
• 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; inhibitor therapy; 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

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肾上腺素受体阻滞剂（α阻滞剂）是放松肌肉张力以改善的第一线治疗 尿路症状较低的患者（LUTS）的排尿 前列物。类固醇5A-还原酶抑制剂（5ARI）阻止二氢睾丸激素（DHT）的局部产生 代表唯一通过腔上皮细胞凋亡来缩小前列腺体积的疗法。结合 这两种疗法都很昂贵，具有不必要的副作用，并且无法完全降低症状的风险 进展。这些数据表明，我们尚未针对调节BPH的各种病原体 进展。 了解5ARI抗性的分子发病机理是对 NIDDK前列腺研究的战略计划。可变药物反应与 组织病理学特征很差。我们提出了一种创新的方法来解构 普遍的5ARI抗性表型的分子发病机理：腺结节。 关于BPH发病机理的相互矛盾的数据很大程度上是由于缺乏全面的翻译 人体组织研究通过将标本分为组织病理学类别的异质性。我们 在此处，请注意约60％的患者可观察到的腺结节表型，并展示两个关键点 在我们的初步数据中：1）患者的雄激素的LC-MS/MS/MS 5ARI水平表明5ARIS正在运作 减少结节中的DHT，但未能诱导腔上皮细胞凋亡，表明5ARI耐药性；和 2）来自5ARI抗性结节的腔上皮的RNA-Seq显示出较高的Notch途径活性。我们将测试 腔上皮凹口信号传导驱动人类BPH中5ARI抗性结节形成的假设 三个关键证据：1）MRI将在5ARI之前和之后对患者进行顺序进行 治疗以识别腺结节是否回落； 2）5ARI耐药的结节性手术标本 将通过LC-MS/MS和组织病理学检查患者，以使DHT独立性与Notch相关 活动; 3）具有异位缺口激活的腺结节外植体和转基因动物将被处理为 确定Notch抑制是否会感知前列腺进行5ARI治疗。成功完成我们的目标 将建立5ARI抗性的分子和表型分类和非侵入性的临床工具 5ARI耐药性腺结节的患者歧视。 关联 关于BPH患者如何失败5ARI疗法的新见解，可以识别新的方法 BPH治疗中的药物治疗。

项目成果

Pathologic HIF1α signaling drives adipose progenitor dysfunction in obesity.

• DOI: 10.1016/j.stem.2020.12.008
• 发表时间: 2021-04-01
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Shao M;Hepler C;Zhang Q;Shan B;Vishvanath L;Henry GH;Zhao S;An YA;Wu Y;Strand DW;Gupta RK
• 通讯作者: Gupta RK

Editorial Comment.

编辑评论。

• DOI: 10.1097/ju.0000000000001640.01
• 发表时间: 2021
• 期刊: The Journal of urology
• 作者: Bauer,ScottR;Huang,Alison
• 通讯作者: Huang,Alison