Glycoprotein Biomarkers for Early Detection of Aggressive Prostate Cancer

 描述(申请人提供)：前列腺癌是最常见的癌症类型，也是美国男性癌症死亡的第二大原因。前列腺癌检测和治疗的一个主要问题是，我们目前没有方法可靠地区分侵袭性前列腺癌和非侵袭性前列腺癌。这导致前列腺癌患者遭受严重的不必要的痛苦。我们假设侵袭性前列腺癌细胞中特定的糖蛋白或其糖基化改变可以作为区分侵袭性前列腺癌患者和非侵袭性前列腺癌患者的生物标志物。我们建议在四个具体目标中开发新的糖蛋白生物标记物，可以检测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组学和质谱法分析侵袭性癌症和非侵袭性癌症患者的尿糖蛋白，以确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EDRN网络中前列腺癌尿液样本的独立测试集中额外尿液样本中的候选糖蛋白进行有针对性的分析，来验证已识别的候选尿糖蛋白。在目标3中，我们将利用目标1和目标2中识别和验证的糖蛋白生物标记物，开发高灵敏度、特异性和高通量的基于选择反应监测的检测方法，作为非侵入性尿液检测，并验证侵袭性前列腺癌生物标记物的检测性能。我们将进一步确定验证测试在主动监测计划中检测侵袭性前列腺癌患者的临床实用性。在目标4中，我们将建立和优化与糖蛋白相关的侵袭性前列腺癌组织的免疫组织化学分析方法，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织化学检测作为基于活检的组织检测在主动监测计划中早期发现侵袭性前列腺癌患者的临床应用价值。如果成功，识别和验证的生物标记物将由EDRN生物标记物参考实验室(BRL)和临床验证中心(CVC)进行回顾性和前瞻性研究。能够区分侵袭性和非侵袭性前列腺癌的生物标志物将使患有侵袭性前列腺癌的男性能够在疾病的早期接受适当的治疗，并防止非侵袭性前列腺癌患者过度治疗。

 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.