Pancreatic Cancer Protein Biomarkers for Early Detection

用于早期检测的胰腺癌蛋白质生物标志物

• 批准号: 7669384
• 负责人: Teresa A Brentnall
• 金额: $ 49.03万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-22 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669384
• 关键词: ANXA2 gene; Accounting; Algorithms; Biological; Biological Assay; Biological Markers; Blood; Blood Tests; Cancer Control; Cancer Patient; Carcinoma in Situ; Cell Membrane Proteins; Cells; Data; Detection; Development; Disease; Ductal; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Evaluation; Extracellular Protein; Future; Galectin 1; Immunohistochemistry; Integrins; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Measures; Membrane Proteins; Methodology; Methods; Outcome; Pancreas; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Pancreatitis; Patients; Performance; Pharmaceutical Preparations; Post-Translational Protein Processing; Proteins; Proteomics; Research Personnel; Role; Serum; Specificity; Symptoms; Technology; Testing; Therapeutic Intervention; Tissue Microarray; Tissues; Validation; Western Blotting; base; cancer cell; chemotherapy; extracellular; improved; outcome forecast; overexpression; programs; response marker; tumor; tumorigenesis; vaccine development; validation studies

DESCRIPTION (provided by applicant): Pancreatic cancer is a uniformly lethal disease because most patients have no symptoms until the cancer has spread and become inoperable. Moreover, once the cancer has formed, chemotherapy offers only minimal improvement in survival. Cancers that are 2 cm or smaller have a much better survival outcome than those that are larger. We propose to develop a serum based early detection test for pancreatic cancer. Nearly all serum cancer biomarker tests are based on the detection of proteins. Therefore, we will use proteomics technology to identify the proteins that are specific to pancreatic cancer and pre-cancer. Our preliminary data is exciting: 1) we have already identified and quantified 656 proteins in pancreatic cancer tissue, of which 90 proteins were up-regulated and 61 were down-regulated in cancer by at least a 2-fold change. 2) Validation studies to date suggest that the proteomics measurements are robust and accurate. The proteins have been analyzed with regard to function, nearly one quarter are extracellular/membrane proteins- thus excellent candidates for pancreatic cancer biomarker development (membrane proteins are shed into the blood). 3) Two of the discovered protein biomarkers, Annexin II and Integrin B1, have been further investigated; both of these proteins have marked over-expression in cancer cells, but not in normal pancreatic ducts or in non-ductal pancreatic cells when evaluated by tissue array and immunohistochemistry. 4) One of the proteins, Galectin 1, has been validated by western blotting and then developed into an ELISA. Galectin 1 could distinguish pancreatic cancer versus normal sera with 100% accuracy in preliminary testing. 5) We have developed a MALDI-TOF-TOF methodology for measuring proteins directly from serum, so that ELISA's would eventually not be necessary for biomarker detection. In this proposal, we describe our methods for the comprehensive development of candidate pancreatic cancer biomarkers and the algorithm that will be used to determine which biomarkers are best suited for development into a clinically useable test. The studies proposed here have the potential to significantly change the outcome in a disease that has made minimal headway in the past 100 years. The use of proteomics technology has enormous potential. Our proposed studies can lead to: earlier diagnosis- improving the prognosis of this deadly disease; better understanding of tumorigenesis in pancreatic cancer; targeted proteins for future therapeutic interventions including new drug/vaccine development; development of disease response markers.

描述（由申请人提供）：胰腺癌是一种普遍致命的疾病，因为大多数患者在癌症扩散并无法手术之前没有任何症状。此外，一旦癌症形成，化疗对生存的改善只能很小。 2 厘米或更小的癌症比那些更大的癌症有更好的生存结果。我们建议开发一种基于血清的胰腺癌早期检测方法。几乎所有血清癌生物标志物测试都是基于蛋白质的检测。因此，我们将利用蛋白质组学技术来鉴定胰腺癌和癌前病变特有的蛋白质。我们的初步数据令人兴奋：1）我们已经鉴定并定量了胰腺癌组织中的 656 种蛋白质，其中 90 种蛋白质在癌症中上调，61 种下调至少 2 倍的变化。 2) 迄今为止的验证研究表明蛋白质组学测量是稳健且准确的。这些蛋白质已经进行了功能分析，近四分之一是细胞外/膜蛋白，因此是胰腺癌生物标志物开发的绝佳候选者（膜蛋白会流入血液中）。 3）对已发现的两个蛋白质生物标志物Annexin II和Integrin B1进行了进一步研究；当通过组织阵列和免疫组织化学评估时，这两种蛋白在癌细胞中显着过度表达，但在正常胰管或非导管胰腺细胞中没有。 4) 其中一种蛋白质半乳糖凝集素 1 已通过蛋白质印迹法验证，然后开发为 ELISA。在初步测试中，半乳糖凝集素 1 能够以 100% 的准确度区分胰腺癌和正常血清。 5) 我们开发了一种 MALDI-TOF-TOF 方法，用于直接测量血清中的蛋白质，因此生物标志物检测最终不再需要 ELISA。在本提案中，我们描述了全面开发候选胰腺癌生物标志物的方法，以及用于确定哪些生物标志物最适合开发为临床可用测试的算法。这里提出的研究有可能显着改变一种在过去 100 年来进展甚微的疾病的结果。蛋白质组学技术的应用具有巨大的潜力。我们提出的研究可以带来： 早期诊断——改善这种致命疾病的预后；更好地了解胰腺癌的肿瘤发生；用于未来治疗干预的靶向蛋白质，包括新药/疫苗的开发；疾病反应标记物的开发。