Validation of biomarkers for early diagnosis and risk prediction of pancreatic neoplasms

胰腺肿瘤早期诊断和风险预测的生物标志物验证

• 批准号: 10375653
• 负责人: Surinder K. Batra
• 金额: $ 61.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-17 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375653
• 关键词: Abdomen; Benign; Biliary; Biological Assay; Biological Markers; Biological Specimen Banks; Blinded; Blood; CA-19-9 Antigen; Carcinoma; Clinical; Consensus; Cyst; Cyst Fluid; Cystic Lesion; Cystic Neoplasm; Cytology; Development; Diagnosis; Disease; Distant Metastasis; Early Detection Research Network; Early Diagnosis; Evaluation; Excision; Exhibits; Fine needle aspiration biopsy; Funding; Future; Goals; Gold; Guidelines; High grade dysplasia; Histologic; Image; International; Intestines; Laboratories; Laboratory Study; Lead; Lesion; Liquid substance; MUC5AC gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Methods; Morbidity - disease rate; Mucinous; Mucins; Nature; Obstruction; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Cyst; Pancreatic Diseases; Pancreatic cystic neoplasia; Patients; Performance; Predictive Value; Primary Neoplasm; Process; Prognosis; Proteins; Protocols documentation; Reporting; Research Personnel; Resectable; Resected; Risk; Risk Assessment; Sampling; Screening for cancer; Sensitivity and Specificity; Series; Slide; Specimen; Stomach; Survival Rate; Time; Tissues; Unresectable; Validation; base; biomarker panel; biomarker validation; cancer risk; candidate marker; chronic pancreatitis; clinical biomarkers; design; disease diagnosis; disorder control; early detection biomarkers; high risk; improved; innovation; mortality; mortality risk; novel; overexpression; overtreatment; pancreatic cancer patients; pancreatic neoplasm; phase III trial; premalignant; prevent; prospective; public health relevance; risk prediction; sample collection; serial imaging; success; tumor; validation studies

 DESCRIPTION (provided by applicant): A majority of pancreatic cancer (PC) patients (> 80%) present with an unresectable primary tumor with distant metastasis at the time of diagnosis due to its asymptomatic nature and lack of methods for early detection. While the overall 5-year survival rate of PC is dismal, significantly better outcomes have been reported for early stage smaller tumors. PC is believed to progress through a series of histological changes and recent estimates indicate that these changes require 15-20 years to develop into invasive metastatic disease, hence providing a window of opportunity to intervene. While early diagnosis is an obvious strategy to improve the survival of PC patients, lack of non-invasive biomarkers for risk prediction of precursor lesions or early stage invasive disease impedes our ability to diagnose PC during this "window. Premalignant cystic lesions of the pancreas offer unique opportunity for early diagnosis. To meet the EDRN stated goal of performing a validation study for early cancer detection and risk assessment likely to yield meaningful results within 5 years, we propose an innovative approach that could lead to the development of a clinically useful biomarker in this time frame. Additionally, we propose to study cystic neoplasms since IPMN and MCN offer a unique opportunity to identify pancreatic premalignant lesions and serve as a target for early detection strategies. The candidate biomarkers studies in our application have been identified and evaluated over the past 5 years in EDRN-funded biomarker developmental laboratories (BDLs). Studies from the laboratories of participating investigators have conclusively established that mucin overexpression is a hallmark of pancreatic cancer and have identified biomarkers (MUC5AC and its 2 glycoforms, MUC4 and a glycoform of endorepellin) that can effectively distinguish a) patients with resectable PC patients from patients with benign pancreatic diseases; b) mucinous and non- mucinous cysts; c) high-grade from moderate- and low-grade mucinous cysts and d). high-risk intestinal type IPMNs and low risk gastric type IPMNs. The overall objective of this CVC proposal is to demonstrate the ability of the aforementioned biomarkers to distinguish pancreatic adenocarcinoma (PC) patients from healthy controls, patients with benign biliary obstruction and chronic pancreatitis (CP), and to identify those cysts with high malignant potential. We have a large number of high quality, well-characterized specimens from patients with pancreatic disease and diseased controls that were collected and processed following protocols developed through the EDRN. Two specific aims are proposed. Aim 1 will use available samples from our biospecimen repository to evaluate MUC5AC and MUC4 as biomarkers to distinguish pancreatic adenocarcinoma (PC) patients from healthy controls, and from patients with benign biliary obstruction and chronic pancreatitis (CP). Aim 2 will determine if our biomarkers can identify those cysts with high lethal potential from those with a low risk for malignant transformation.

 描述（由申请人提供）：大多数胰腺癌（PC）患者（> 80%）在诊断时存在不可切除的原发性肿瘤伴远处转移，这是由于其无症状性质和缺乏早期检测方法。虽然PC的总体5年生存率令人沮丧，但据报道，早期较小肿瘤的结局明显更好。PC被认为通过一系列组织学变化而进展，最近的估计表明这些变化需要15-20年才能发展成侵袭性转移性疾病，因此提供了干预的机会窗口。虽然早期诊断是改善PC患者生存率的明显策略，但缺乏用于预测前驱病变或早期浸润性疾病风险的非侵入性生物标志物阻碍了我们在此“窗口期”诊断PC的能力。胰腺癌前囊性病变为早期诊断提供了独特的机会。为了满足EDRN规定的目标，即进行早期癌症检测和风险评估的验证研究，可能在5年内产生有意义的结果，我们提出了一种创新的方法，可以在此时间范围内开发出临床有用的生物标志物。此外，我们建议研究囊性肿瘤，因为IPMN和MCN提供了一个独特的机会，以确定胰腺癌前病变，并作为早期检测策略的目标。我们申请中的候选生物标志物研究已经在过去5年中在EDRN资助的生物标志物开发实验室（BDL）中进行了鉴定和评估。参与研究者实验室的研究已最终确定粘蛋白过度表达是胰腺癌的标志，并已确定了生物标志物（MUC 5AC及其2种糖型，MUC 4和内排斥素的糖型），其可以有效区分a）患有可切除PC的患者与患有良性胰腺疾病的患者; B）粘液性和非粘液性囊肿; c）从中度和低度粘液性囊肿到高级粘液性囊肿，以及d）.高风险肠型IPMN和低风险胃型IPMN。该CVC提案的总体目标是证明上述生物标志物区分胰腺癌（PC）患者与健康对照、良性胆道梗阻和慢性胰腺炎（CP）患者的能力，并鉴定具有高恶性潜能的那些囊肿。我们有大量来自胰腺疾病患者和疾病对照的高质量、特征良好的标本，这些标本是根据EDRN制定的方案收集和处理的。提出了两个具体目标。目的1将使用来自我们的生物标本库的可用样本来评估MUC 5AC和MUC 4作为生物标志物，以区分胰腺癌（PC）患者与健康对照，以及良性胆道梗阻和慢性胰腺炎（CP）患者。目标2将确定我们的生物标志物是否可以识别那些具有高致死潜力的囊肿与那些具有低恶性转化风险的囊肿。