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

分析前列腺癌中 PSA 和其他糖生物标志物的尿液糖基化

• 批准号: 7386271
• 负责人: Lewis K. Pannell
• 金额: $ 16.54万
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386271
• 关键词: Affect; Age; Archives; Benign; Benign Prostatic Hypertrophy; Biological Assay; Biological Markers; Blood; Body Fluids; Breast; Cancer Patient; Cells; Clinic; Clinical; Clinical Trials; Computer software; Computing Methodologies; Condition; Daily; 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; Numbers; Patients; Pattern; Plasma; Polysaccharides; Population; Post-Translational Protein Processing; Prostate; Prostate-Specific Antigen; Prostatic hypertrophy; 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; Standards of Weights and Measures; 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）：尿液是一种容易获得但很大程度上被丢弃的泌尿生殖系统癌症生物标志物的潜在来源。癌症的生物标志物出现在尿液中，即使是肺癌和乳腺癌等癌症。我们在健康个体的尿液中观察到前列腺特异性抗原（PSA）和前列腺酸性磷酸酶（PAP）的显著水平，与早期的一些发现一致。虽然PSA是目前前列腺癌（PC）的生物标志物，但其可靠性受到个体之间基线水平差异以及各种可用试剂盒测量结果不一致的影响。目前迫切需要建立一种临床相关的检测方法，用于检测前列腺癌、良性前列腺增生（BPH）产生的PSA（和PAP）以及健康细胞释放的PSA（和PAP），从而可靠地用于前列腺癌的早期检测、预后和监测。PSA和PAP都是糖基化的，而糖基化的变化与癌症密切相关。最近的报告显示，在癌症中PSA的糖基化发生变化，但在不同的体液中测量（前列腺癌的血清和健康人的精液），并且仅在一名患者中有效。我们开发了一种方法（GlycoMatic）来分析富集蛋白中单个位点的糖基化。我们将改进分离方法，以丰富PSA， PAP和其他可能在临床样品中检测到的前列腺特异性糖蛋白。我们将测试该技术与健康个体尿液样本中添加的标准物和标准物的对照，获得可重复性测定的能力，以及在不理想条件下储存时糖蛋白的稳定性。为了消除任何可归因于遗传或表观遗传组成的变化，将使用60名正常志愿者的尿液建立个体PSA和PAP糖基化谱的变化。有关年龄和种族等变量的资料将纳入分析，这些分析将由少数民族人口组成。将对60名前列腺癌和良性前列腺增生（BPH）患者的PSA和PAP糖基化谱进行测定，并与健康志愿者进行比较。获得用于临床试验的糖基化谱的能力是一个新的领域。因此，将建立计算方法，以显示个体内，每种疾病分类内数据的可靠性，并与疾病状态，Gleason评分和PSA血清水平相关。这项研究开辟了新的领域，将建立生物标志物蛋白糖基化谱在癌症早期检测、预测和监测中的临床适用性。它还将识别和区分由于种族而造成的任何变化。前列腺特异性抗原（PSA）是前列腺癌（PC）早期检测和监测的一种成熟的检测方法。尽管如此，由于个体之间基础水平的差异，以及各种可用试剂盒测量结果的不一致性，其测定受到阻碍。癌症中产生的PSA经过修饰（糖基化），这项有限的临床试验将确定两者之间的差异，并确定这些差异是否足以明确区分前列腺癌产生的PSA与健康前列腺正常产生的PSA。前列腺酸性磷酸酶是前列腺癌早期的糖蛋白生物标志物，也将进行类似的研究。分析将在尿液中进行，从而有可能对PC进行自我管理测试。