Glycoprotein Biomarkers for Early Detection of Aggressive Prostate Cancer

 描述（由申请人提供）：前列腺癌是最常见的癌症类型，并且是美国男性癌症死亡的第二大贡献者。前列腺癌检测和治疗的主要问题是我们目前没有可靠区分侵袭性前列腺癌和非侵袭性前列腺癌的方法。这会给前列腺癌患者带来不必要的痛苦。我们假设，在侵袭性前列腺癌细胞中特异性改变的特定糖蛋白或其糖基化可用作区分侵袭性前列腺癌患者与非侵袭性前列腺癌患者的生物标志物。我们提出了四个具体目标，以开发新的糖蛋白生物标志物，可以检测手术前尿液或活检组织中的侵袭性癌症。在目标1中，我们将使用高通量糖蛋白质组学和质谱分析来自侵袭性癌症和非侵袭性癌症患者的尿糖蛋白，以鉴定与侵袭性前列腺癌相关的糖蛋白。在目标2中，我们将通过对来自EDRN网络的前列腺癌尿液标本的独立测试集中的额外尿液样本的候选糖蛋白进行靶向分析来验证所识别的候选尿糖蛋白。在目标3中，我们将开发高灵敏度、特异性和高通量的基于ELISA或质谱的选择性反应监测测定法，作为使用目标1和目标2中鉴定和验证的糖蛋白生物标志物的非侵入性尿液检测，并验证侵袭性前列腺癌生物标志物检测的性能。我们将进一步确定经验证的检测在主动监测计划中检测侵袭性前列腺癌患者的临床效用。在目标4中，我们将开发和优化与侵袭性前列腺癌组织相关的糖蛋白的免疫组织化学检测，并使用组织芯片验证这些组织糖蛋白。然后，我们将进一步确定免疫组化检测作为基于活检的组织检测在积极监测计划中早期检测侵袭性前列腺癌患者的临床实用性。如果成功，EDRN生物标志物参考实验室（BRL）和临床验证中心（CVC）将在回顾性和前瞻性研究中对鉴定和验证的生物标志物进行检测。能够区分侵袭性和非侵袭性前列腺癌的生物标志物将允许患有侵袭性前列腺癌的男性在其疾病过程中更早地接受适当的治疗，并防止患有非侵袭性前列腺癌的男性过度治疗。

 DESCRIPTION (provided by applicant): Prostate cancer is the most prevalent type of cancer and it is the second highest contributor to cancer death among men in the U.S. 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. This leads to significant unnecessary suffering among prostate cancer patients. We hypothesize that specific glycoproteins or their glycosylation specifically altered in aggressive prostate cancer cells can be used as biomarkers to distinguish patients with aggressive from those with non-aggressive prostate cancer. We propose in four specific aims to develop novel glycoprotein biomarkers that can detect aggressive cancer in pre-surgical urine or biopsy tissues. In Aim 1, we will analyze urinary glycoproteins from patients with aggressive cancer and non-aggressive cancer using high throughput glycoproteomics and mass spectrometry to identify glycoproteins associated with aggressive prostate cancer. In Aim 2, we will validate the identified candidate urinary glycoproteins by targeted analysis of candidate glycoproteins from additional urine samples in independent testing sets of prostate cancer urine specimens from the EDRN network. In Aim 3, we will develop highly sensitive, specific, and high throughput ELISA or mass spectrometry based selective reaction monitoring assays as noninvasive urine tests using the glycoprotein biomarkers identified and validated from Aim 1 and Aim 2 and validate the performance of the tests for aggressive prostate cancer biomarkers. We will further determine the clinical utility of the validated tests to detect patients with aggressive prostate cancer in active surveillance program. In Aim 4, we will develop and optimize the immunohistochemistry assays for the glycoproteins associated aggressive prostate cancer tissues and validate these tissue glycoproteins using tissue microarrays. We will then further determine the clinical utility of the immunohistochemistry assays as biopsy based tissue tests for the early detection of patients with aggressive prostate cancer in active surveillance program. If successful, the identified and validated biomarkers will be tested by EDRN biomarker reference laboratory (BRL) and clinical validation center (CVC) in retrospective and prospective studies. Biomarkers capable of distinguishing aggressive from nonaggressive prostate cancer will allow men with aggressive prostate cancer to receive appropriate treatment earlier in the course of their diseases and prevent men with non- aggressive prostate cancer from overtreatment.