Longitudinal Proteomic and Metabolomic Predictors of Pancreatic Cyst Malignant Progression and Early Stage Pancreatic Cancer

胰腺囊肿恶性进展和早期胰腺癌的纵向蛋白质组学和代谢组学预测因子

• 批准号: 10377358
• 负责人: Christian Maximillian Schmidt
• 金额: $ 64.88万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377358
• 关键词: Age; Benign; Biological; Biological Markers; CA-19-9 Antigen; Cancer Center; Clinical; Clinical Management; Clinical/Radiologic; Colorectal; Consensus; Cyst; Cyst Fluid; Data; Diagnosis; Dinoprostone; Disease; Dysplasia; Early Diagnosis; Enrollment; Enzyme-Linked Immunosorbent Assay; Excision; Guidelines; Image; Incidence; Indiana; International; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Modeling; Mucinous Neoplasm; Natural History; Nested Case-Control Study; Operative Surgical Procedures; Ovarian; PTPRJ gene; Pancreatic Cyst; Pancreatic Ductal Adenocarcinoma; Papillary; Pathology; Patients; Physicians; Pilot Projects; Plant Roots; Plasma; Population; Prognosis; Prospective cohort study; Prostate; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Proteins; Proteomics; Race; Radiology Specialty; Resected; Risk; Sampling; Specificity; Surgical Pathology; THBS2 gene; TIMP1 gene; Testing; Time; Universities; Unnecessary Surgery; Utah; base; cancer invasiveness; cohort; cost; density; follow-up; high risk; improved; metabolomics; mortality; pancreatic cancer patients; predictive marker; prospective; protein metabolite; public health relevance; radiological imaging; risk prediction model; sex; surveillance study; tumor progression

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) has a dire prognosis mainly due to its late diagnosis. It is vital to identify early-stage PDAC and its precursors. One such precursor is intraductal papillary mucinous neoplasm (IPMN), a type of pancreatic cyst. International consensus guidelines recommend resection of IPMN with high malignancy risk and surveillance of IPMN without surgical indications. Based on radiologic/clinical findings, the guidelines have a dismal specificity for discerning benign from malignant IPMN and a poor accuracy of predicting IPMN malignant progression. It is urgent to identify biomarkers that predict malignant progression of presumed “low-risk” IPMN. The primary objective of the proposed study is to identify and validate protein and metabolite signatures and their longitudinal changes which can discriminate IPMN malignant progression and detect early-stage PDAC. Supported by preliminary data, our central hypothesis is that the levels and trajectories of such signatures in plasma and/or pancreatic cyst fluid are predictive of IPMN malignant progression and early-stage PDAC. Specific Aims: 1. Investigate plasma and cyst fluid levels and trajectories of proteomic biomarkers and metabolomics signatures for prediction of IPMN malignant progression in a prospective surveillance cohort. 1A: A global proteomics and metabolomics study of pancreatic cyst fluid in 160 IPMN surgical patients will be conducted to identify proteins and metabolites associated with high-grade and invasive IPMN. 1B: Top proteins identified from 1A and 6 proteins (THBS2, PGE2, LRG1, TIMP1, C1RL, & PTPRJ) discovered in our preliminary studies will be measured in serial plasma (n=3) and cyst fluid (n=~2.5) samples from 500 IPMN patients under surveillance. 1C: Top metabolites identified from 1A and 4 plasma metabolites correlated with IPMN dysplasia grade in our R21 study will be quantified in the 1B population. The levels and trajectories of proteins and metabolites measured in 1B and 1C will be evaluated in relation to IPMN malignant progression. 1D: A risk prediction model for IPMN malignant progression will be built from proteins and metabolites identified and validated in 1B and 1C, CA 19-9, and clinical/imaging features. 2. Evaluate levels and trajectories of plasma proteomic biomarkers and metabolomics signatures for detection of early- stage PDAC in a PRoBE-compliant case-control study nested in the PLCO cohort. 2A: proteins identified in 1A and 6 biomarkers listed in 1B will be measured in serial prediagnostic plasma samples (n=up to 3) from 242 PDAC cases (incl. 80 early-stage cases) and 242 matched controls. 2B: In the 2A population, top metabolites identified from 1A, 4 metabolites described in 1C, and 5 metabolites predicting early-stage PDAC in our pilot studies will be determined. 2C: A risk prediction model for early-stage PDAC will be developed from proteins and metabolites identified in 2A and 2B, CA 19-9, and clinical/imaging features. Our expected results will allow clinicians to timely resect IPMNs with high malignant potential before progression to invasive cancer, while avoiding unnecessary surgeries. Detecting early-stage PDAC will substantially increase patient survival.

项目摘要/摘要 胰腺导管腺癌（PDAC）的预后很可怕，这主要是由于其晚期诊断。至关重要 识别早期PDAC及其前体。这样的前体是导管内乳头状粘液肿瘤 （IPMN），一种胰腺囊肿。国际共识指南建议切除IPMN 没有手术适应症的IPMN的恶性风险和监视。基于放射学/临床发现， 指南对从恶性IPMN辨别良性的良性具有令人沮丧的特异性，并且准确性差。 预测IPMN恶性进展。迫切需要确定预测的生物标志物 假定“低风险” IPMN。拟议研究的主要目的是识别和验证蛋白质， 代谢物特征及其纵向变化，可以区分IPMN恶性进展和 检测早期PDAC。在初步数据的支持下，我们的中心假设是水平和 血浆和/或胰腺囊肿流体中这种特征的轨迹可预测IPMN恶性肿瘤 进展和早期PDAC。具体目的：1。研究血浆和囊肿流体水平和轨迹 蛋白质组学生物标志物和代谢组学特征，用于预测A 前瞻性监视队列。 1A：一项全球蛋白质组学和代谢组学研究 将进行160名IPMN手术患者，以鉴定与高级相关的蛋白质和代谢物 和侵入性IPMN。 1B：从1A和6个蛋白质鉴定的顶部蛋白质（THBS2，PGE2，LRG1，TIMP1，C1RL，＆＆ 在我们的初步研究中发现的PTPRJ）将以串行血浆（n = 3）和囊肿液（n = 〜2.5）进行测量。 来自500名IPMN患者的样品在监视下。 1C：从1a和4个血浆鉴定的顶部代谢产物 在我们的R21研究中，与IPMN发育不良级相关的代谢物将在1B人群中进行量化。这 将根据IPMN评估以1B和1C测量的蛋白质和代谢物的水平和轨迹 恶性进展。 1D：IPMN恶性进展的风险预测模型将由蛋白质构建 以及在1B和1C，CA 19-9以及临床/成像特征中鉴定和验证的代谢产物。 2。评估 血浆蛋白质组学生物标志物和代谢组学特征的水平和轨迹，用于检测早期 嵌套在PLCO队列中的符合探头的病例对照研究中的PDAC。 2a：在1a中鉴定的蛋白质 1B中列出的6个生物标志物将在242的串行预发现等离子体样品（n = 3）中测量 PDAC病例（包括80例早期病例）和242个匹配的对照。 2B：在2A人群中，顶级代谢产物 从1a中鉴定出1C中描述的4个代谢产物，5个代谢物预测我们的飞行员早期PDAC 将确定研究。 2C：早期PDAC的风险预测模型将从蛋白质开发 以及在2A和2B，CA 19-9以及临床/成像特征中鉴定出的代谢产物。我们的预期结果将允许 临床医生及时在进展为侵入性癌症之前及时分辨出具有高恶性潜力的IPMN，而 避免不必要的外科手术。检测早期PDAC将大大增加患者的生存率。