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

基本信息

批准号：
10427409
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
项目类别：
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/10427409
关键词：
Advocate Attention Benign Benign Prostatic Hypertrophy Biochemistry Biological Assay Biological Markers Biopsy Blinded Blood Breast Cancer Etiology Cancer Patient Cells Cessation of life Clinical Development Diagnosis Diagnostic Diagnostic tests Digital Rectal Examination Disease FDA approved Fingers Fluorescence Genomics Goals Gold 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 North America Pathology Patients Peptides Predictive Value Procedures Prostate Prostate-Specific Antigen Proteins 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 novel optical imaging overexpression overtreatment prostate biopsy prostate cancer cell receptor serum PSA stem tumor molecular fingerprint ultrasound urinary

项目摘要

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：尽管在了解前列腺癌（PCa）的基因组和分子基础方面取得了进展，但前列腺癌（PCa）仍然是美国男性中最常诊断出的实体恶性肿瘤，也是癌症的第二大原因死亡。目前，唯一确定的诊断 PCa 的方法是侵入性经直肠前列腺超声检查活检。大多数（>66%）活检显示良性病理，但牺牲了患者的发病率和医疗保健美元。因此，仍然需要一种简单且非侵入性的方法来解决这一问题。明确诊断前列腺癌，确定其是侵袭性、惰性还是良性，并帮助指导其治疗。分子谱分析时代对血液中脱落的恶性PCa细胞的基因组分析引起了广泛关注和尿液。在 FDA 批准的两种此类测定中，PCA3 和 SelectMDx，在 DRE 后收集尿液，恶性通过 PCa 的多重基因组指纹分离和表征细胞。虽然有创新性，但 PCA3 测试并不是广泛使用，主要是由于其广泛的敏感性、特异性、阳性预测 (PPV) 和 (62%-94%) 阴性预测值（NPV）。此外，SelectMDx 和经常提倡的血清的临床效用 4Kscore测试，仍不确定。有大量文献证明 VPAC 受体在 PCa 细胞上表达。与 NIH/NCI 合作在支持下，我们设计并用 Cu-64 标记了 VPAC 特异性肽，使我们能够成功地对 PCa 进行成像人类。然后我们假设 PCa 细胞在没有前列腺刺激的情况下从 PCa 患者的尿液中脱落通过 DRE，可以通过靶向 VPAC 受体进行光学成像，使用标记有相同的肽荧光团。我们对从 PCa、BPH 患者收集的超过 250 个去识别化尿样的初步结果和正常情况下，令人鼓舞（敏感性> 98％）并且与我们的假设一致。在本次调查中我们建议获取开发这种有前景的非侵入性药物所需的关键信息尿液检测作为 PCa 诊断测试。我们的具体目标是 1) 确定敏感性、特异性、阳性已知患有已知疾病的男性的分子尿检测的预测值（PPV）和阴性预测值（NPV） PCa 和阴性对照； 2) 检验该检测在治疗患有以下疾病的患者中的功效既往 PCa 活检呈阴性，但 PSA 持续升高，并计划进行 TRUS 活检； 3) 确定 a) 恶性细胞是否占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) 脱落的恶性细胞中的 VPAC 蛋白数量与疾病的侵袭性； 4) 评估分子尿检测在管理中的作用接受主动监测的患者； 5) 确定尿液储存是否需要防腐剂。这简单、可靠且患者友好的单重检测将 a) 检测活性、侵袭性或惰性 PCa，b) 拯救患者避免过度诊断和过度治疗，c) 减少不必要的活检和相关患者的数量发病率，以及 d) 节省数百万医疗费用。