Refinement and Discovery of Nuclear Matrix Protein Markers for Colorectal Cancer

结直肠癌核基质蛋白标记物的完善和发现

• 批准号: 8693603
• 负责人: KENNETH W. KINZLER
• 金额: $ 59.54万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-07 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693603
• 关键词: Antibodies; Area; Biological Assay; Biological Markers; Blinded; Clinical; Colon Carcinoma; Colorectal Cancer; Data; Detection; Development; Early Detection Research Network; Error Sources; Evaluation; Excision; Funding; Goals; Institution; Laboratories; Liver; Malignant Neoplasms; Measurement; Metastatic Neoplasm to the Liver; Nuclear Matrix-Associated Proteins; Outcome; Phase; Population; Population Characteristics; Positioning Attribute; Proteins; Recurrence; Sampling; Series; Serum; Specimen; Testing; Time; Tissues; Validation; Work; advanced disease; assay development; base; colorectal cancer screening; novel marker; patient population; prognostic; programs; research clinical testing; research study; success; validation studies

DESCRIPTION (provided by applicant): The focus of this proposal is to continue development of a unique panel of colon cancer associated nuclear matrix proteins (NMPs), discovered and developed during our previous EDRN-sponsored, Biomarker Development Laboratory funding. NMPs offer the potential serum-based biomarkers for the early detection of colorectal cancer. This work has progressed substantially from testing of un-blinded single institution convenience samples all the way to testing of blinded, EDRN sponsored multi-institution reference sets. Markers were tested in different laboratory settings, cancer subtypes, and patient population characteristics. These data provide compelling potential for application in clinical populations. Currently two markers, CCSA-2 and CCSA-4 are poised for Phase ll-lll validation studies. We propose, with the help of established experts in assay development, to further refine those assays to position them for definitive clinical testing. In addition, we will advance NMP markers related to liver metastasis. The two major objectives 1. To OPTIMIZE AND REFINE the CCSA-2 and CCSA-4 assays and test them in a series of small scale experiments to position them for definitive evaluation within the EDRN mechanism. In specific, we aim to (a) develop robust assays for the accurate and precise measurement of CCSA-2 and CCSA-4; (b) test the assays under a variety of clinical circumstances and conditions to understand, and anticipate sources of error and potential problems in implementation that might be encountered when testing the assays on a larger scale. The goal of this first objective is to deliver two assays to validation with ample preliminary testing to maximize the potential for success in the EDRN program. 2. To develop NMP markers for liver metastasis. We have identified proteins in liver metastasis tissue specimens that are neither present in adjacent uninvolved liver nor in liver from normal donors. These proteins are prime candidates for assay development for markers of advanced disease. We propose (a) to isolate, characterize and develop antibodies for serum detection of liver metastasis proteins, (b) to evaluate these antibodies in appropriate clinical specimens for eventual delivery for EDRN validation.

描述（由申请人提供）：该提案的重点是继续开发一组独特的结肠癌相关核基质蛋白 (NMP)，这些蛋白质是在我们之前 EDRN 赞助的生物标志物开发实验室资助期间发现和开发的。 NMP 为结直肠癌的早期检测提供了潜在的基于血清的生物标志物。这项工作从非盲式单一机构便利样本测试一直到盲式、EDRN 赞助的多机构参考集测试取得了重大进展。在不同的实验室环境、癌症亚型和患者群体特征中测试了标记物。这些数据为临床人群的应用提供了令人信服的潜力。目前，CCSA-2 和 CCSA-4 两种标记物正准备进行 II-III 期验证研究。我们建议，在测定开发领域知名专家的帮助下，进一步完善这些测定，以将其用于最终的临床测试。此外，我们还将推进与肝转移相关的NMP标志物。两个主要目标 1. 优化和完善 CCSA-2 和 CCSA-4 检测，并在一系列小规模实验中对其进行测试，以将其定位在 EDRN 机制内进行明确评估。具体而言，我们的目标是 (a) 开发稳健的检测方法，以准确、精确地测量 CCSA-2 和 CCSA-4； (b) 在各种临床环境和条件下测试测定，以了解并预测在大规模测试测定时可能遇到的错误来源和实施中的潜在问题。第一个目标是通过充分的初步测试提供两种检测方法进行验证，以最大限度地发挥 EDRN 计划成功的潜力。 2. 开发肝转移的NMP标志物。我们已经在肝转移组织样本中鉴定出蛋白质，这些蛋白质既不存在于邻近的未受累肝脏中，也不存在于正常供体的肝脏中。这些蛋白质是晚期疾病标志物检测开发的主要候选蛋白。我们建议 (a) 分离、表征和开发用于肝转移蛋白血清检测的抗体，(b) 在适当的临床样本中评估这些抗体，以便最终交付用于 EDRN 验证。