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.

摘要 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的一线治疗方法 对有下尿路症状(LUT)的患者排尿，但对较小的非纤维化患者最有效 前列腺。类固醇5a-还原酶抑制剂(5ARI)可阻断局部产生的双氢睾酮(DHT)， 代表了通过腔上皮细胞凋亡来缩小前列腺体积的唯一疗法。组合 这两种疗法都很昂贵，都有不想要的副作用，而且无法完全减缓出现症状的风险。 进步。这些数据表明，我们还没有针对调节良性前列腺增生症的各种病因。 进步。 了解5ARI耐药的分子发病机制是优先建议的 NIDDK前列腺研究战略计划。可变药物反应和药物反应之间的潜在联系 对其组织病理学特征的研究较少。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：腺结节的分子发病机制。 关于BPH发病机制的相互矛盾的数据在很大程度上是由于缺乏全面的翻译 通过将标本归入组织病理学类别来解释异质性的人体组织研究。我们 这里重点关注我们60%的患者中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)患者雄激素的LC-MS/MS和5ARI水平表明5ARI正在发挥作用 减少结节中的DHT，但不能诱导管腔上皮细胞凋亡，提示5ARI耐药； 2)5ARI耐药结节的腔上皮细胞RNA-SEQ显示Notch途径活性升高。我们将测试 管腔上皮Notch信号驱动5ARI耐药结节形成的假说 三个关键证据：1)对患者进行5ARI前后的MRI检查 治疗以确认腺结节是否消退；2)抗ARI的结节外科标本 将对患者进行LC-MS/MS和组织病理学检查，以确定DHT独立性与Notch的相关性 活性；3)腺结节外植体和异位Notch激活的转基因动物将被处理 确定Notch抑制是否使前列腺对5ARI治疗敏感。圆满完成我们的目标 将建立5ARI耐药的分子和表型分类，并成为非侵入性的临床工具 5ARI抵抗性腺结节患者的鉴别。 相关性 对BPH患者如何失败5ARI治疗的新见解为发现新的治疗方法带来了巨大的希望 前列腺增生症的内科治疗。

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