Noninvasive, Uniplex, Molecular, Pathomic Urinary Assay for Detection of Prostate Cancer

用于检测前列腺癌的无创、单一、分子、病理性尿液分析

• 批准号: 10663194
• 负责人: MATHEW laxman THAKUR
• 金额: $ 58.2万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663194
• 关键词: Advocate; Attention; Benign; Benign Prostatic Hypertrophy; Biochemistry; Biological Assay; Biological Markers; Biopsy; Blinded; Blood; Breast; Cancer Etiology; Cancer Patient; Cell Separation; Cells; Cessation of life; Clinical; Development; Diagnosis; Diagnostic; Diagnostic tests; Digital Rectal Examination; Disease; FDA approved; Fingers; Fluorescence; Friends; Genomics; Goals; HOXC6 gene; Healthcare; Histology; Human; Image; Indolent; Investigation; Label; Life; Literature; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Messenger RNA; Methods; Molecular; Molecular Profiling; Morbidity - disease rate; Names; Non-Invasive Detection; North America; Pathology; Patients; Peptides; Predictive Value; Printing; Procedures; Prostate; Prostate-Specific Antigen; Proteins; Rectum; Research Personnel; Role; Sampling; Schedule; Screening for Prostate Cancer; Sensitivity and Specificity; Serology; Serum; Solid; Specificity; Surface; Testing; Translating; Transrectal Ultrasound; United States National Institutes of Health; Urine; VIPR1 gene; cancer biomarkers; cancer cell; cancer diagnosis; clinical practice; design; detection assay; diagnostic biomarker; efficacy evaluation; fluorophore; in vivo; innovation; malignant breast neoplasm; men; minimally invasive; noninvasive diagnosis; novel; optical imaging; overexpression; overtreatment; prostate biopsy; prostate cancer cell; receptor; rectal; serum PSA; stem; tumor molecular fingerprint; ultrasound; urinary

Abstract: Despite the advances in understanding its genomic and molecular basis, prostate cancer (PCa) remains the most commonly diagnosed solid malignancy in men in the US and the second leading cause of cancer death. Currently, the only established method to diagnose PCa is an invasive transrectal ultrasound prostate biopsy. The majority (>66%) of biopsies show benign pathology at the expense of patient morbidity and healthcare dollars. There remains, therefore, an unmet need for a simple and non-invasive approach that will definitively diagnose PCa, determine if it is aggressive, indolent or benign and help guide its management. The era of molecular profiling has drawn much attention to genomic analysis of malignant PCa cells shed in blood and urine. In two such assays, the PCA3 and SelectMDx approved by FDA, urine is collected after DRE, malignant cells isolated and characterized by multiplex genomic finger prints of PCa. Although innovative, PCA3 test is not widely used, primarily due to its wide range (62%-94%) of sensitivity, specificity, positive predictive (PPV) and negative predictive value (NPV). Furthermore, the clinical utility of SelectMDx and a frequently advocated serum 4Kscore test, remains uncertain. There is robust literature demonstrating that VPAC receptors are expressed on PCa cells. With NIH/NCI support, we designed and labeled a VPAC specific peptide with Cu-64 that allowed us to image PCa successfully in humans. We then hypothesized that PCa cells, shed in voided urine of PCa patients, without prostate stimulation by DRE, can be imaged optically by targeting VPAC receptors, using the same peptide labeled with a fluorophore. Our preliminary results of >250 de-identified urine samples, collected from patients with PCa, BPH and normal cases, are encouraging (sensitivity >98%) and are consistent with our hypothesis. In this investigation we propose to obtain critical information that will be required for the development of this promising noninvasive urine assay as a PCa diagnostic test. Our specific aims are 1) To determine sensitivity, specificity, positive predictive (PPV), and negative predictive value (NPV) of the molecular urinary assay for men with known PCa and negative controls; 2) To examine the efficacy of the assay in the management of patients with previous negative biopsy for PCa but have persistently elevated PSA and are scheduled for TRUS biopsy; 3) To establish if a) the malignant cells as a percent of total cells shed in the urine, b) the fluorescence intensity around malignant cells, and c) the VPAC protein quantity in shed malignant cells correlate with the aggressiveness of the disease; 4) To assess the role of this molecular urine assay in the management patients on active surveillance; and 5) To determine if a preservative is required for urine storage. This simple, reliable and patient-friendly uniplex assay will a) detect active, aggressive or indolent PCa, b) save patients from over diagnosis and over treatment, c) reduce the number of unnecessary biopsies and associated patient morbidity, and d) save millions of healthcare dollars.

摘要：尽管了解其基因组和分子基础的进步，前列腺癌（PCA） 仍然是美国男性最常见的稳健恶性肿瘤，也是癌症的第二大原因 死亡。目前，诊断PCA的唯一既定方法是侵入性的转直肠超声前列腺 活检。大多数（> 66％）活检表现出良性病理学，以患者的发病率和 医疗保健美元。因此，仍然需要一种简单且无创的方法的需求 明确诊断PCA，确定其是侵略性，懒惰还是良性，并帮助指导其管理。 分子分析的时代吸引了对血液中恶性PCA细胞的基因组分析的关注 和尿液。在两个这样的测定中，PCA3和SelectMDX经FDA批准，在DRE后收集尿液，恶性 细胞分离并以PCA的多重基因组手指印刷为特征。虽然是创新的，但PCA3测试不是 广泛使用，主要是由于其敏感性，特异性，阳性预测性（PPV）和 负预测值（NPV）。此外，SelectMDX和经常提倡的血清的临床实用性 4Kscore测试，仍然不确定。 有强大的文献表明VPAC受体在PCA细胞上表达。与NIH/NCI 支持，我们设计并用CU-64标记了VPAC特异性肽，该肽使我们能够在 人类。然后，我们假设PCA细胞在PCA患者的无效尿液中脱落，而没有前列腺刺激 通过DRE，可以使用与A标记的相同肽通过靶向VPAC受体来光学成像 荧光团。我们的初步结果> 250个去识别的尿液样本，从PCA，BPH患者收集 正常情况和正常情况是令人鼓舞的（敏感性> 98％），并且与我们的假设一致。在这项调查中 我们建议获得开发这种有希望的无创的关键信息 尿液分析作为PCA诊断测试。我们的具体目的是1）确定灵敏度，特异性，积极 预测性（PPV）和针对已知男性的分子尿测定的负预测值（NPV） PCA和阴性对照； 2）检查测定在患者管理中的功效 PCA的先前阴性活检，但PSA持续升高，计划进行TRUS活检； 3）确定a）恶性细胞是尿液中脱落的总细胞的百分比，b）荧光 恶性细胞周围的强度，c）脱落恶性细胞中的VPAC蛋白质量与 疾病的侵略性； 4）评估该分子尿液测定在管理中的作用 主动监视的患者； 5）确定尿液储存是否需要防腐剂。这 简单，可靠且患者友好的独立测定法将a）检测活跃，侵略性或懒惰的PCA，b）保存患者 c）从诊断过度和治疗过度治疗，减少不必要的活检和相关患者的数量 发病率和d）节省数百万美元的保健资金。