Circulating Biomarkers and Imaging for Early Detection of Pancreatic Cancer

项目总结 迫切需要早期发现胰腺癌的生物标志物。然而，单个分子 以人群为基础的筛查所需的敏感性和特异性尚未发现。CA-19-9 已经进行了广泛的研究，但未能证明早期预测的价值 检测和诊断。虽然包括蛋白质组、基因组和转录组在内的许多平台 已经利用了各种方法，并确定了生物标志物候选，但还没有一个平台或分子 在大型盲人筛查中成功验证。我们已经走上了功能基因组的道路 以胰腺和其他器官最早改变的基因组间隔为靶点的生物标志物发现方法 与吸烟相关的癌症，重点关注与癌症相关的关键细胞通路中涉及的生物标记物。我们 已经确定了一个经过两次盲目验证的“移民签名”和生物标志物小组 包括NCI-EDRN胰腺癌早期疾病和良性健康的参考集 控制。结果表明，我们的生物标志物小组提高了CA19-9的检测性能 无症状的早期胰腺癌在各验证平台上产生显著结果。我们有 开发了胰腺癌的血浆miRNA生物标记物面板，并在多项试验中进行了验证。这个 我们的生物标志物组合显示出高灵敏度和高特异性来检测早期胰腺 癌症。我们将进一步完善这一早期生物标志物小组和一种新的风险评分方法，以对 一般人群和高危人群进行筛查。改进的面板将在大型回顾中得到验证 根据探头设计进行胰腺癌早期诊断的前瞻性队列研究。为了让我们 在转移前识别早期疾病，服从治疗性干预，我们将利用一只小鼠- 从血浆和血浆外切体中开发综合生物标志物以检测晚期的人类方法 晚期癌症发生前的先驱分期，随后对 诊断前生物标记物小组。我们还将开发一种新的两级筛选策略，经过验证 生物标志物和新的成像工具改变临床管理计划并显著提高存活率 最致命的癌症之一。

PROJECT SUMMARY Biomarkers for the early detection of pancreatic cancer are urgently needed. However, individual molecules with the sensitivity and specificity needed for population-based screening have not been discovered. CA-19-9 has been studied extensively and yet has failed to demonstrate the predictive value necessary for early detection and diagnosis. Although many platforms, including proteomic, genomic and transcriptomic approaches have been utilized and biomarker candidates identified, no one platform or molecule has been successfully validated in large blinded population screens. We have taken a functional genomic pathways approach to biomarker discovery targeting the earliest genomic intervals altered in pancreatic and other smoking related cancers, focusing on biomarkers involved in critical cancer relevant cellular pathways. We have identified a “migration signature” and biomarker panel that has gone through two blinded validations including the NCI-EDRN pancreatic cancer reference set of early stage disease and benign and healthy controls. Results indicate that our panel of biomarkers improves the performance of CA19-9 to detect asymptomatic early stage pancreatic cancer yielding significant results across validations platforms. We have developed plasma miRNA biomarker panels for pancreatic cancer and validated these in multiple trials. The combination of our biomarkers demonstrates high sensitivity and specificity to detect early stage pancreatic cancer. We will further refine this early stage biomarker panel and a novel risk score approach to stratify the general population and at risk population for screening. Refined panels will be validated in large retrospective and prospective cohorts for early detection of pancreatic cancer according to ProBE design. In order that we identify early stage disease prior to metastasis, amenable to curative intervention, we will utilize a mouse- human approach to develop integrated biomarkers profiles from plasma and plasma exosomes to detect late precursor stage PanINs prior to development of advanced cancer with subsequent validation for a prediagnostic biomarker panel. We will also develop a novel two tiered screening strategy with validated biomarkers and novel imaging tools to change the clinical management plan and significantly improve survival of one of the most deadly cancers.