Mayo Clinic Prospective Resource for Biomarker Validation and Early Detection of Pancreatic Cancer

梅奥诊所生物标志物验证和胰腺癌早期检测的前瞻性资源

• 批准号: 10524819
• 负责人: Shounak Majumder
• 金额: $ 81.24万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524819
• 关键词: Address; Age; Algorithms; Biological Assay; Biological Markers; Biological Specimen Banks; Biometry; Blinded; Blood; Blood Proteins; Blood specimen; CA-19-9 Antigen; Cancer Detection; Cancer Etiology; Cancer-Predisposing Gene; Centers of Research Excellence; Cessation of life; Characteristics; Clinic; Collection; Cyst Fluid; DNA; DNA Markers; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Discrimination; Disease; Early Diagnosis; Epidemiology; Evaluation; Familial pancreatic cancer; Family; Family history of; Gastroenterology; General Population; Genetic; Genetic Predisposition to Disease; Germ-Line Mutation; Goals; Grant; Guidelines; Incidence; Individual; Infrastructure; Knowledge; Leadership; Longitudinal cohort; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Measurable; Methodology; Methods; Non-Malignant; Pancreas; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Participant; Patients; Pennsylvania; Performance; Phase; Plasma; Population; Procedures; Proteins; Protocols documentation; Race; Recording of previous events; Resources; Risk; Risk Factors; Sampling; Screening for cancer; Smoking; Standardization; Survival Rate; Symptoms; THBS2 gene; Testing; Time trend; Tissues; United States; Universities; Validation; base; biobank; biomarker development; biomarker panel; biomarker validation; blood product; case control; clinical effect; clinical translation; cohort; design; diagnostic accuracy; disorder control; early detection biomarkers; early onset; experience; family genetics; high risk; improved; individual patient; innovation; kindred; member; multidisciplinary; mutational status; new technology; novel; novel marker; novel strategies; pancreatic ductal adenocarcinoma model; patient variability; phase 2 designs; phase 2 study; phase 2 testing; phase 3 study; phase 3 testing; prospective; protein biomarkers; recruit; sample collection; screening; sex; stem cell model; tool

Pancreatic ductal adenocarcinoma (PDAC) is typically detected at late stage due to absence of a cancer screening strategy, with concomitant poor survival rates. Detection of PDAC at an early stage positively impacts survival, and currently screening in eligible high-risk individuals (HRIs) defined by family history and germline mutation status is considered best practice. The overall goal of this proposal is to use knowledge gained during the last grant period to considerably enhance our ability to develop and validate the diagnostic performance of new blood protein and methylated DNA (MDM) biomarkers for early detection of PDAC, using prospective specimen collection and retrospective blinded evaluation (PRoBE) compliant methods. We hypothesize that a combination of proteins, MDMs, and CA19-9 will accurately identify early stage PDAC in HRIs. We will assess the performance characteristics of our approaches in early stage and pre-diagnostic phase of PDAC and identify approaches that are optimized for clinical translation as an early detection tool using HRIs. For over two decades, Mayo Clinic’s prospective biospecimen resources have accrued, using standardized high-quality procedures, well-annotated biospecimens from thousands of PDAC patients including those with germline mutations in pancreas cancer susceptibility genes, high risk members in familial pancreatic cancer kindreds, patients with high-risk pancreatic conditions, and healthy controls. We have also launched the PCDC Signature Protocols at our center. Among those at risk with biospecimens who we have followed longitudinally over two decades, incident PDAC cases have developed, enabling us to utilize novel approaches to address the challenges and better design PRoBE phase 3 studies. Based on our findings in the last grant period, we now focus on tailoring samples for PRoBE phase 2 studies and characterizing performance to improve phase 3 studies. Our approach will allow us to assess, for example, variability in biomarker expression for intended use HRI settings, and temporality of biomarker expression to improve the ability to detect early onset PDAC. Our Specific Aims are to: 1) Accrue formal biospecimen sets from blood sample products and pancreatic cyst fluid suitable for PCDC biomarker studies; 2) Leverage our past knowledge and experience to develop new biomarker panels using tailored phase 2 designs and incorporating covariates to refine detection (age, sex, race, smoking, personal history of diabetes mellitus, symptoms at diagnosis) to optimize detection; and 3) Evaluate needed performance parameters that will inform the design of a successful phase 3 study for PDAC in a surveillance setting of HRIs. Our multidisciplinary team is committed to continue its leadership and contribution to the PCDC organization to advance the early detection of pancreatic cancer. Our project leverages existing infrastructures and biospecimen banks of pancreatic cancer and other pancreatic diseases at Mayo Clinic and University of Pennsylvania, and it will extend new prospective collections of blood and pancreatic cyst fluid from patients, contributing to PCDC Signature Protocol cohorts and a PCDC central biorepository.

由于没有癌症，胰腺导管腺癌 (PDAC) 通常在晚期才被发现 筛查策略，伴随着低生存率。早期检测 PDAC 可产生积极影响 生存率，目前对根据家族史和种系定义的合格高风险个体 (HRI) 进行筛查 突变状态被认为是最佳实践。该提案的总体目标是利用期间获得的知识 最后的资助期大大增强了我们开发和验证诊断性能的能力 新的血液蛋白和甲基化 DNA (MDM) 生物标志物，用于早期检测 PDAC，利用前瞻性 符合样本采集和回顾性盲法评估 (PRoBE) 的方法。我们假设一个 蛋白质、MDM 和 CA19-9 的组合将准确识别 HRI 中的早期 PDAC。我们将评估 我们的方法在 PDAC 的早期阶段和预诊断阶段的性能特征，并确定 作为使用 HRI 的早期检测工具，针对临床转化进行了优化的方法。二十多年来， 梅奥诊所使用标准化的高质量程序积累了前瞻性的生物样本资源， 来自数千名 PDAC 患者的注释明确的生物样本，其中包括那些具有种系突变的患者 胰腺癌易感基因、胰腺癌家族高危成员、胰腺癌患者 高风险胰腺疾病和健康对照。我们还在以下网址推出了 PCCDC 签名协议： 我们的中心。在我们二十年来长期跟踪的那些面临生物样本风险的人中， 事件 PDAC 案例不断涌现，使我们能够利用新颖的方法来应对挑战和 更好地设计 PRoBE 第 3 期研究。根据我们在上一个资助期的发现，我们现在专注于定制 用于 PRoBE 第 2 阶段研究的样本和表征性能以改进第 3 阶段研究。我们的方法 例如，我们可以评估预期用途 HRI 设置的生物标志物表达的变异性，以及 生物标志物表达的暂时性，以提高检测早发性 PDAC 的能力。我们的具体目标是： 1) 从适合 PCCDC 的血液样本产品和胰腺囊肿液中获取正式的生物样本组 生物标志物研究； 2) 利用我们过去的知识和经验来开发新的生物标记物组合 量身定制的第二阶段设计并结合协变量来完善检测（年龄、性别、种族、吸烟、个人 糖尿病病史、诊断时的症状）以优化检测； 3) 评估所需的性能 这些参数将为在 HRI 监测环境中成功设计 PDAC 3 期研究提供信息。 我们的多学科团队致力于继续发挥领导作用并为 PCCDC 组织做出贡献，以实现 推进胰腺癌的早期发现。我们的项目利用现有的基础设施和生物样本 梅奥诊所和宾夕法尼亚大学的胰腺癌和其他胰腺疾病库，以及 将扩大患者血液和胰腺囊肿液的新前瞻性采集，为 PCCDC 做出贡献 签名协议队列和 PCCDC 中央生物样本库。