Glycoprotein biomarkers for the early detection of aggressive prostate cancer

描述（由申请人提供）：前列腺癌是美国男性最常见的癌症类型（今年约有192,280例新病例），也是美国男性癌症死亡的第二大原因（今年将有27,360人死于前列腺癌）。前列腺癌检测和治疗的一个主要问题是，我们目前还没有办法使用现有的生物标志物来可靠地区分侵袭性前列腺癌和非侵袭性前列腺癌。这给前列腺癌患者带来了大量不必要的痛苦，并导致了大量不必要的医疗支出。我们假设特定的糖蛋白和糖蛋白的聚糖修饰可以用来区分组织和血清中的侵袭性和非侵袭性前列腺癌。我们提出了四个具体目标，开发新的糖蛋白生物标志物，可以检测原发性组织和术前血清中的侵袭性癌症。在目的1中，我们将分析来自转移性、侵袭性、非侵袭性和正常前列腺组织的聚糖和糖蛋白，以确定与侵袭性前列腺癌相关的糖蛋白。在Aim 2中，我们将为Aim 1中鉴定的候选糖肽开发高灵敏度、特异性和高通量的基于MS的SRM检测方法。我们将优化SRM分析方法，确定其分析性能，并构建SRM数据库，使该分析方法可供科研界使用。在Aim 3中，我们将使用Aim 2中开发的SRM测定法在其他前列腺癌组织中验证侵袭性前列腺癌的糖蛋白，并使用组织微阵列验证这些组织糖蛋白。在Aim 4中，我们将使用SRM检测来确定组织中哪些已验证的糖肽可以在患者的血清中检测到，因此可以用作血清检测。然后，我们将把SRM分析应用于血清样本，并开发验证的多变量模型，用于使用血清检测侵袭性前列腺癌。此外，我们将使用一组独立的前列腺癌血清测试来验证这些标记物和多变量模型。如果成功，鉴定和验证的生物标志物将由EDRN生物标志物参考（BRL）和临床验证（CVC）实验室在回顾性和前瞻性研究中进行测试。能够区分侵袭性前列腺癌和非侵袭性前列腺癌的生物标志物，可以将非侵袭性前列腺癌患者与过度治疗区分开来，并允许侵袭性前列腺癌患者在疾病早期接受适当的治疗。

DESCRIPTION (provided by applicant): Prostate cancer is the most prevalent type of cancer for U.S. men (about 192,280 new cases this year), and it is the second highest contributor to cancer death among men in the U.S. (27,360 will die of it this year). A major issue in prostate cancer detection and therapy is that we currently have no method to reliably distinguish aggressive prostate cancer from non-aggressive prostate cancer using available biomarkers. This leads to significant unnecessary suffering among prostate cancer patients and leads to massive unnecessary health care expenditures. We hypothesize that specific glycoproteins and glycan modifications of glycoproteins can be used to distinguish aggressive from non-aggressive prostate cancer in tissue and serum. We propose in four specific aims to develop novel glycoprotein biomarkers that can detect aggressive cancer in primary tissues and pre-surgical serum. In Aim 1, we will analyze glycans and glycoproteins from metastatic, aggressive cancer, non-aggressive cancer, and normal prostate tissues to identify glycoproteins associated with aggressive prostate cancer. In Aim 2, we will develop highly sensitive, specific, and high throughput MS based SRM assays for the candidate glycopeptides identified from Aim 1. We will optimize the SRM assays and determine their analytical performance, and construct an SRM database and make the assay available to the research community. In Aim 3, we will use the developed SRM assays from Aim 2 to verify the glycoproteins for aggressive prostate cancer in additional prostate cancer tissues and validate these tissue glycoproteins using tissue microarrays. In Aim 4, we will use the SRM assays to determine which of the verified glycopeptides in tissues can be detected in patient's sera, and therefore can be used as serum tests. Then, we will apply the SRM assays to the serum samples and develop validate multivariate models for detecting aggressive prostate cancer using serum tests. In addition, we will validate these markers and multivariate models using an independent testing set of prostate cancer serum. If successful, the identified and validated biomarkers will be tested by EDRN biomarker reference (BRL) and clinical validation (CVC) laboratories in retrospective and prospective studies. Biomarkers capable of distinguishing aggressive from nonaggressive prostate cancer would present men with non-aggressive prostate cancer from overtreatment, and could allow men with aggressive cancer to receive appropriate treatment earlier in the course of their diseases. SRM = selected reaction monitoring