Profiling Urine Glycosylation of PSA and other Glyco-Biomarkers in Prostate Cance

前列腺癌中 PSA 和其他糖生物标志物的尿液糖基化分析

• 批准号: 7576898
• 负责人: Lewis K. Pannell
• 金额: $ 19.85万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-29 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7576898
• 关键词: Affect; Age; Archives; Benign Prostatic Hypertrophy; Biological Assay; Biological Markers; Blood; Body Fluids; Breast; Cancer Patient; Cells; Clinic; Clinical; Clinical Trials; Computer software; Computing Methodologies; Data; Databases; Detection; Development; Disease; Early Diagnosis; Epigenetic Process; Ethnic Origin; Fucose; Genetic; Genitourinary system; Gleason Grade for Prostate Cancer; Glycoproteins; Hand; Individual; Letters; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Manuals; Mass Spectrum Analysis; Measurement; Measures; Methods; Minority; Monitor; Patients; Pattern; Plasma; Polysaccharides; Population; Post-Translational Protein Processing; Prostate; Prostate-Specific Antigen; Proteins; Proteome; Proteomics; Published Comment; Publishing; Regression Analysis; Reporting; Research; Research Personnel; Resources; Running; Sampling; Self-Administered; Seminal fluid; Serum; Sialic Acids; Site; Source; Specimen; Staging; Structure; Techniques; Testing; Time; Urine; Urogenital Cancer; Variant; Visual; analytical method; base; clinical application; cohort; disease classification; glycosylation; healthy volunteer; outcome forecast; prognostic; prostatic fraction Acid phosphatase isoenzyme; sialylation; volunteer

DESCRIPTION (provided by applicant): Urine represents an easily available yet largely discarded potential source of biomarkers of urogenital cancers. Biomarkers of cancer appear in urine, even from remote cancers such as lung and breast. We observed significant levels of both prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) in the urine from healthy individuals, consistent with some earlier findings. While PSA is the current biomarker for prostate cancer (PC), its reliability is hampered by variations in the baseline level between individuals, and the inconsistency in measurements made by the variety of kits available. There is an urgent need for establishing a clinically pertinent assay for the characterization of PSA (and PAP) produced in PC, benign prostatic hyperplasia (BPH) and that released by healthy cells, one that can be reliably used for the early detection, prognosis and monitoring of prostate cancer. Both PSA and PAP are glycosylated and changes in glycosylation go hand-in-hand with cancer. Recent reports have shown that changes occur in the glycosylation of PSA in cancer but were measured in different body fluids (serum for PC and seminal fluid for healthy), and effectively in only one patient. We have developed a method (GlycoMatic) for profiling glycosylation at individual sites in enriched proteins. We will refine isolation approaches to enrich the PSA, PAP and such other prostate-specific glycoproteins as may be detected in clinical samples. We will test the technique against standards and standards spiked into urine samples from healthy individuals, the ability to get reproducible determinations, and the stability of the glycoproteins when stored under less than ideal conditions. To eliminate any changes attributable to genetic or epigenetic make-up, variations in the individual PSA and PAP glycosylation profiles will be established using urines from 60 normal volunteers. Information on variables such as age and ethnicity will be factored into the analyses which will result from a population with a significant minority component. The PSA and PAP glycosylation profiles will be determined for a cohort of 60 (of each) PC and benign prostatic hyperplasia (BPH) patients and compared to that from the healthy volunteers. The ability to obtain glycosylation profiles for clinical trials is a new field. Thus, computational methods will be established that show the reliability of the data within individuals, within each classification of the disease, and correlated with disease status, Gleason score and PSA serum levels. This research breaks new ground and will establish the clinical applicability for the use of glycosylation profiles of biomarker proteins in the early detection, prediction and monitoring of cancer. It will also identify and distinguish any changes due to ethnicity. Prostate specific antigen (PSA) is a well-established test for the early detection and monitoring of prostate cancer (PC). Despite this, its determination is hampered by variation in the basal level between individuals, and the inconsistency in measurements made by the variety of kits available. PSA produced in cancer is modified (glycosylated) and this limited clinical trial will establish the differences, and determine if these are specific enough to clearly distinguish PC produced PSA from that normally produced by a healthy prostate. Prostatic acid phosphatase, an earlier glycoprotein biomarker of prostate cancer, will be similarly studied. Analyses will be performed in urine, leading to the possibility of a self-administered test for PC.

描述（由申请人提供）：尿液代表了一种易于获得但在很大程度上丢弃的泌尿生殖器癌症的潜在来源。癌症的生物标志物也出现在尿液中，甚至来自肺和乳房等遥远的癌症。我们观察到来自健康个体的尿液中的前列腺特异性抗原（PSA）和前列腺酸性磷酸酶（PAP），这与一些早期发现一致。虽然PSA是目前的前列腺癌（PC）生物标志物，但其可靠性受到个人之间基线水平的变化的阻碍，以及可用多种套件的测量值不一致。迫切需要建立对PC，良性前列腺增生（BPH）中产生的PSA（和PAP）的临床相关测定，并由健康细胞释放，该测定方法可可靠地用于早期检测，预后和对前列腺癌的监测。 PSA和PAP都是糖基化的，并且糖基化的变化与癌症息息相关。最近的报道表明，在癌症中PSA的糖基化中发生了变化，但在不同的体液（PC的血清和精液液的健康状态）中进行了测量，仅在一名患者中有效地测量。我们已经开发了一种方法（Glycomatic），用于在富集蛋白的各个位点进行糖基化。我们将完善分离方法，以丰富PSA，PAP和其他前列腺特异性糖蛋白，如临床样品中可能检测到的。我们将根据来自健康个体的尿液样本，获得可重复测定的能力以及糖蛋白在不理想的条件下储存时的尿液样本的标准和标准测试。为了消除归因于遗传或表观遗传构成的任何变化，将使用60名正常志愿者的尿液来确定单个PSA和PAP糖基化谱的变化。关于年龄和种族等变量的信息将纳入分析中，这将是由具有少数群体组成部分的人群产生的。 PSA和PAP糖基化谱将确定为60（每个）PC的队列和良性前列腺增生（BPH）患者，并与健康志愿者相比。获得临床试验糖基化谱的能力是一个新领域。因此，将建立计算方法，以显示疾病的每个分类中数据中数据的可靠性，并与疾病状况，格里森评分和PSA血清水平相关。这项研究破坏了新的基础，并将在早期检测，预测和监测癌症中建立生物标志物蛋白糖基化谱的临床适用性。它还将确定并区分由于种族而引起的任何变化。前列腺特异性抗原（PSA）是对前列腺癌（PC）的早期检测和监测的良好测试。尽管如此，它的决定受到个人之间基础水平的差异的阻碍，以及可用的各种试剂盒进行的测量的不一致性。在癌症中产生的PSA经过修饰（糖基化），该有限的临床试验将确定差异，并确定这些差异是否足够特异，可以清楚地将产生的PSA与通常由健康前列腺产生的PC区分开。前列腺磷酸酶是前列腺癌的早期糖蛋白生物标志物，将类似地研究。分析将在尿液中进行，从而导致对PC进行自我管理测试的可能性。