Serum Proteomic Biomarkers for Colon & Pancreatic Cancer

描述（由申请人提供）：根据RFA CA-04-006“早期检测研究网络：生物标志物发展实验室”（EDRN/BDL）的要求，本续期申请提出了一项以匹兹堡大学癌症研究所（UPCI）为中心的综合多学科生物标志物发现和验证研究，重点是胃肠道恶性肿瘤，特别是结肠癌和胰腺癌。提出了两个主要项目：(1)早期检测CRC的核基质蛋白；(2)早期检测胰腺癌的Luminex Multianalyte Profiling （LabMAP(r)）和SELDI-TOF-MS血清蛋白质组学分析。这两个项目都是基于生物标志物的发现和我们目前的EDRN/BDL拨款中开发的强有力的初步数据，包括一个由具有生物统计学/生物信息学必要专业知识的教师支持的基础癌症研究人员和临床医生团队。项目1将进一步表征、评估和验证CRC中表达的一组独特的核基质蛋白（NMPs）。在初步数据中，NMP的先导生物标志物CC2在结直肠癌患者的血清中升高。该项目的一个关键目标是开展更广泛的1/2期验证研究，以评估该生物标志物在基于血清的CRC早期检测中的性能。我们正在开发的其他nmp，在癌前（腺瘤）和恶性组织中具有不同的表达谱，将进一步表征和评估作为早期疾病和/或风险的潜在生物标志物。项目2将扩展我们的初步数据，这些数据由EDRN补充资金开发，使用两种尖端的蛋白质组学分析技术获得：1)独特的Luminex xMAP(r)多路血清学生物标志物，包括多种胰腺癌相关细胞因子，趋化因子，血管生成和生长因子及其受体，以及针对胰腺抗原的循环抗体；2) SELDI-TOF-MS，这两种方法都能在血清中对胰腺癌患者和病例匹配的对照组进行强有力的区分。该项目将对这些分析技术进行广泛的1/2期验证研究，用于胰腺癌的早期检测和疾病的临床复发。最后，作为一个平行和集中的生物标志物发现目标，我们将确定提供SELDI-TOF-MS谱的疾病分类的关键诊断肽/蛋白的身份。这些研究项目将在整合的UPCI EDRN/BDL的背景下进行，由EDRN PI继续领导，他在癌症生物标志物和临床蛋白质组学研究方面拥有丰富的经验。该团队是一群杰出的临床和转化癌症研究人员，专注于癌症生物标志物的发现、评估和验证。这些努力将有力地支持EDRN的研究和临床目标。

DESCRIPTION (provided by applicant): This renewal application, in response to the RFA CA-04-006 "The Early Detection Research Network: Biomarker Developmental Laboratories" (EDRN/BDL), proposes an integrated multi-disciplinary biomarkers discovery and validation study centered at the University of Pittsburgh Cancer Institute (UPCI) focused on GI malignancies, specifically colon and pancreatic cancer. Two major Projects are proposed: (1) Nuclear Matrix Proteins for Early Detection of CRC, and (2) Luminex Multianalyte Profiling (LabMAP(r)) and SELDI-TOF-MS Serum Proteomic Profiling for Early Detection of Pancreatic Cancer. Both projects are firmly based on biomarker discoveries and strong preliminary data developed in our current EDRN/BDL grant and include a team of basic cancer researchers and clinicians supported by faculty with requisite expertise in biostatistics/bioinformatics. Project 1 will further characterize, evaluate, and validate a set of unique nuclear matrix proteins (NMPs) which are expressed in CRC. In preliminary data, the lead NMP biomarker, CC2, is elevated in the serum of CRC patients. A key objective of this Project is to undertake a more extensive Phase 1/2 validation study to assess the performance of this biomarker for serum-based early detection of CRC. Other NMPs in our development pipeline, with a varying spectrum of expression in pre-malignant (adenomas) and malignant tissue, will be further characterized and evaluated as potential biomarkers of early disease and/or risk. Project 2 will extend our preliminary data, developed with EDRN supplemental funds, obtained using two cutting-edge proteomic profiling technologies: 1) a unique panel of Luminex xMAP(r) multiplexed serologic biomarkers comprising multiple pancreatic cancer associated cytokines, chemokines, angiogenic and growth factors and their receptors, as well as circulating antibodies against pancreatic antigens; and 2) SELDI-TOF-MS, that both provide robust discrimination, in serum, of pancreatic cancer patients and case-matched controls. This Project will undertake an extensive Phase 1/2 validation study of these profiling technologies for pancreatic cancer early detection and clinical recurrence of disease. Lastly, as a parallel and focused biomarker discovery aim, we will determine the identity of the key diagnostic peptides/proteins that provide disease classification of the SELDI-TOF-MS profiles. These research Projects will be conducted in the context of an integrated UPCI EDRN/BDL, led by the continuing EDRN PI who brings extensive experience in cancer biomarkers and clinical proteomics research. This team is an outstanding and productive group of clinical and translational cancer researchers focused on cancer biomarkers discovery, evaluation, and validation. These efforts will strongly support the research and clinical goals of the EDRN.