MUC4/16 assay for the early diagnosis and management of benign and malignant pancreatic diseases

MUC4/16 检测用于良性和恶性胰腺疾病的早期诊断和治疗

• 批准号: 9409374
• 负责人: MANEESH JAIN
• 金额: $ 19.9万
• 依托单位: SANGUINE DIAGNOSTICS AND THERAPEUTICS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-12 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409374
• 关键词: Adenocarcinoma; Amendment; Archives; Automation; Benign; Biological; Biological Assay; Biological Markers; Blinded; Cancer Patient; Cell surface; Clinical; Cyst; Cyst Fluid; Cystic Lesion; Cystic Neoplasm; Cytology; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Diagnostic radiologic examination; Diagnostic tests; Discrimination; Disease; Distant Metastasis; Ductal Epithelial Cell; Early Diagnosis; Epithelial Cells; Evaluation; Excision; Exhibits; Fine needle aspiration biopsy; Future; Gland; Goals; Image; Immunohistochemistry; Individual; Intervention; Laboratories; Lesion; MUC4 mucin; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Medical center; Methods; Morbidity - disease rate; Mucinous; Mucinous Differentiation; Mucinous Lesion; Mucinous Neoplasm; Mucins; Multicenter Trials; Nature; Nebraska; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Ductal Carcinoma; Pancreatic Intraepithelial Neoplasia; Papillary; Pathology; Patient Selection; Patients; Performance; Phase; Pre-hospital setting; Predictive Value; Predictive Value of Tests; Prevalence; Primary Neoplasm; Probability; Prognostic Marker; Reagent; Reporting; Research Personnel; Resected; Risk; Role; Safety; Sampling; Serous; Serous Lesion; Serum; Slide; Solid; Specificity; Specimen; Staining method; Stains; Survival Rate; Testing; Therapeutic; Time; Tissues; Ultrasonography; Universities; Unresectable; Validation; accurate diagnosis; base; chronic pancreatitis; diagnostic biomarker; differential expression; high risk; interest; noninvasive diagnosis; older patient; pancreas development; patient stratification; prototype; research clinical testing; response; tool; tumor

Abstract The goal of this Fast track application is to develop a non-invasive diagnostic test (based on MUC4 and MUC16 mucins) that can serve as an adjunct to cytological analysis of fine needle aspirates (FNAs) for accurate prediction of malignancy in patients with cystic pancreatic lesions. Due to asymptomatic nature and lack of methods for early detection, > 80% of pancreatic cancer (PC) patients present with an unresectable primary tumor with distant metastasis at the time of diagnosis. While the overall 5 year survival rate of pancreatic cancer is dismal, significantly better outcomes have been reported for smaller tumors detected at an earlier stage. Slow development of PC in conjunction with the better curative response of patients with early disease underscore the need of early detection of pancreatic cancer. Pancreatic cystic lesions, earlier considered to be rare, are increasingly being recognized due to increased number of individuals being subjected to diagnostic imaging; however, their exact prevalence is unknown. These cystic pancreatic lesions have variable malignant potential: while mucinous cystic neoplasms (MCNs) and intraductal pancreatic mucinous neoplasms (IPMNs) have a high probability of developing into malignant lesions, serous cystic neoplasms (SCNs) are considered benign. Despite the critical need, accurate discrimination between high- and low-risk cystic lesions is challenging due to their symptomatic and radiographic similarities. Although cytologic examination of endoscopic ultrasound (EUS) guided fine needle aspirates (FNAs) has emerged as an indispensable part of presurgical evaluation, in practice, 50%–60% of such analyses are inconclusive and unreliable in discriminating between serous and mucinous lesions. Using anti-MUC4 MAb 8G7 generated by our group several studies have established that cell surface mucin MUC4 is promising prognostic and diagnostic biomarker. Further MUC4 and MUC16 exhibited 100% specificity for malignancy in EUS-FNAs containing atypical ductal epithelial cells. The central hypothesis of this proposal Detection of MUC4 and/or MUC16 in pancreatic tissues (EUS FNAs) is positively correlated with the presence of already existing pancreatic cancer or cystic lesions with malignant potential and thus MUC4/16 staining is a powerful tool for the accurate prediction of malignancy and pre-surgical stratification of patients with cystic lesions of the pancreas. Studies proposed for Phase I will result in the development of a prototype kit for MUC4MUC16 IHC (Aim 1) and provide proof of concept in support of the aforementioned hypothesis. Studies proposed in Phase II will validate the significance of MUC4/16 immunostaining in a blinded trial and determine how MUC4/16 expression correlates with the clinical outcome of the solid/cystic pancreatic diseases (Aim 2). Further, we propose to test the prototype kit in a clinical setting (CLIA Lab) to validate performance (Aim 3). Overall, the proposal will lead to the development of a clinical test to stratify patients for surgical intervention or surveillance in the context of pancreatic cystic lesions and PC.

摘要 该快速通道应用程序的目标是开发一种非侵入性诊断测试（基于MUC 4和MUC 16 粘蛋白），其可以用作细针抽吸物（FNA）的细胞学分析的辅助，以准确地检测细胞的粘附。 胰腺囊性病变患者恶性肿瘤的预测。由于无症状的性质和缺乏 早期检测方法，> 80%的胰腺癌（PC）患者存在不可切除的原发性胰腺癌。 在诊断时有远处转移的肿瘤。虽然胰腺癌的5年生存率 虽然这是令人沮丧的，但据报道，在早期阶段检测到的较小肿瘤的结局明显更好。慢 PC的发展与早期疾病患者更好的治疗反应相结合， 胰腺癌的早期诊断胰腺囊性病变，早期被认为是罕见的， 由于接受诊断成像的个体数量增加而越来越多地被认识到; 然而，其确切患病率尚不清楚。这些囊性胰腺病变具有不同的恶性潜能： 而粘液性囊性肿瘤（MCNs）和导管内胰腺粘液性肿瘤（IPMNs）具有较高的 由于浆液性囊性肿瘤（SCN）可能发展为恶性病变，因此被认为是良性的。 尽管迫切需要，准确区分高风险和低风险囊性病变是具有挑战性的， 症状和影像学上的相似性虽然内镜超声细胞学检查 (EUS)引导细针抽吸（FNA）已成为术前评估不可或缺的一部分， 在实践中，50%-60%的此类分析在区分浆液性和非浆液性方面是不确定和不可靠的。 粘液性病变。使用我们小组产生的抗MUC 4单克隆抗体8 G7，几项研究已经确定， 细胞表面粘蛋白MUC 4是有希望的预后和诊断生物标志物。其他MUC 4和MUC 16 在含有非典型导管上皮细胞的EUS-FNAs中，恶性肿瘤的特异性为100%。中央 该建议的假设胰腺组织（EUS FNA）中MUC 4和/或MUC 16的检测是阳性的 与已经存在的胰腺癌或具有恶性潜能的囊性病变相关， 因此MUC 4/16染色是准确预测恶性肿瘤和术前分层的有力工具 胰腺囊性病变的患者。第一阶段拟议的研究将导致制定一个 MUC 4 MUC 16 IHC（Aim 1）的原型试剂盒，并提供支持上述概念的概念证明 假说.在II期中提出的研究将验证MUC 4/16免疫染色在盲法中的意义。 试验并确定MUC 4/16表达如何与实性/囊性胰腺炎的临床结局相关， 疾病（目标2）。此外，我们建议在临床环境（CLIA实验室）中测试原型试剂盒，以验证 性能（目标3）。总的来说，该提案将导致临床试验的发展，以分层患者， 在胰腺囊性病变和PC的背景下进行手术干预或监测。