Development of a panel of multiplex biomarkers for the early detection of pancreatic ductal adenocarcinoma and high-risk lesions

胰腺导管腺癌（PDAC）是一种侵袭性极强的恶性肿瘤，总生存期为5年 的11%。由于其无症状的性质和缺乏早期发现的方法，大多数PDAC患者 （> 85%）存在非局限性肿瘤。这突出了在早期局部阶段检测PDAC的必要性。 导管内乳头状粘液性肿瘤（IPMN）和粘液性囊性肿瘤（MCN）提供了一种独特的 有机会识别癌前病变，作为早期检测策略的目标。兰德尔·布兰德博士 等人提出了一种两步监测方法来早期发现PDAC：1）识别高风险 通过临床评价，PDAC患病率升高接近或高于1%的人群，以及2） 开发血清生物标志物，用于间隔重复检测，以检测监测中的受试者， 增加额外成像的PDAC风险（患病率约10%）。这项提案的目标是确定血清 生物标志物，并开发体外诊断多变量指数测定（IVDMIA），并将其纳入 “通过监测早期发现”工作流程，用于检测早期PDAC及其前驱病变。 这些IVDMIA的预期用途为：1）协助对入选的高风险受试者进行临床评价 在早期发现PDAC的监测，和2）检测PDAC或高风险IPMN的风险上升， 对监测对象进行纵向评价。该项目有五个具体目标：1。发现和开发 通过血清/组织样本的整合蛋白质组学分析的基于血清的PDAC早期检测生物标志物 从早期PDAC，IPMN，良性和健康对照使用多模式和分阶段的方法， 基于组织的蛋白质组学分析和免疫组织化学（IHC）的确证性支持证据 验证2.使用由预定义的预期用途驱动的设计方法， 开发和评价IVDMIA的血清生物标志物是有意义的和实际可行的。3.制定和 优化选定生物标志物的多重分析测定，并将其应用于生成高质量的生物标志物 用于IVDMIA开发和临床评价的数据。4.收集和组装大型临床标本样本 用于IVDMIA算法开发和独立验证的集合。5.参与协作 与其他PCDC-RU的活动。为了取得成功，拟议的项目需要一个多学科，系统 方法和关键技术、数据科学和临床标本资源的支持。我们的团队是 独特的PDAC和IPMN病理学专家团队，用于早期检测、临床化学/分析 用于IVDMIA开发的临床蛋白质组学和统计/机器学习。最 重要的是，团队成员个人和集体都有长期的积极研究历史 在生物标志物开发和转化为临床试验方面取得了成就，包括第一个蛋白质组学 IVDMIA测试通过FDA批准。我们相信，通过这些创新而实用的方法，我们的RU提供了 这是为PCDC网络做出重大贡献并解决关键临床未满足需求的最佳机会。

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with an overall 5-year survival of 11%. Due to its asymptomatic nature and lack of methods for early detection, the majority of PDAC patients (> 85%) present with non-localized tumors. This highlights the need to detect PDAC at an earlier, localized stage. Intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) offer a unique opportunity to identify premalignant lesions to serve as targets for early detection strategies. Dr. Randall Brand and others proposed a two-step surveillance approach for early detection of PDAC: 1) identification of high-risk populations through clinical evaluation with an elevated PDAC prevalence close to or above 1% and 2) development of serum biomarker(s), for repeated testing at intervals to detect subjects in surveillance with a rising risk of PDAC (prevalence ~ 10%) for additional imaging. The goal of this proposal is to identify serum biomarkers and develop in vitro diagnostic multivariate index assays (IVDMIAs) and incorporate them into an “early detection through surveillance” workflow for the detection of early-stage PDAC and its precursor lesions. The intended use of these IVDMIAs are 1) to assist in the clinical evaluation of high-risk subjects to be included in surveillance for the early detection of PDAC, and 2) to detect rising risk of PDAC or high-risk IPMN in the longitudinal evaluation of subjects in surveillance. The project has five specific aims: 1. To discover and develop serum-based PDAC early detection biomarkers through integrated proteomic analysis of serum/tissue samples from early-stage PDAC, IPMN, and benign and healthy controls using a multimodal and phased approach with corroborative supporting evidence from tissue-based proteomic analysis and immunohistochemical (IHC) verification. 2. To use a by-design approach driven by predefined intended uses that are both clinically meaningful and practically feasible to develop and evaluate serum biomarkers for IVDMIAs. 3. To develop and optimize multiplex analytical assays for selected biomarkers and apply them to generate high-quality biomarker data for IVDMIA development and clinical evaluation. 4. To collect and assemble large clinical specimen sample sets for both IVDMIA algorithm development and independent validation. 5. To participate in collaborative activities with other PCDC-RUs. To be successful, the proposed project requires a multi-disciplinary, systems approach and the support of critical technology, data science, and clinical specimen resources. Our team is a unique ensemble of experts in PDAC and IPMN pathology for early detection, clinical chemistry/assay development, clinical proteogenomics, and statistical/machine learning for IVDMIA development. Most importantly, the team members individually and collectively all have a long-standing history of active research with accomplishments in biomarker development and translation into clinical tests, including the first proteomic IVDMIA test cleared by the FDA. We believe with these innovative yet practical approaches, our RU offers the best opportunity to make significant contributions to the PCDC network and address critical clinical unmet needs.