Employing mouse models to translate early detection of pancreas cancer

利用小鼠模型转化胰腺癌的早期检测

• 批准号: 9097660
• 负责人: RAGHU KALLURI
• 金额: $ 54万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097660
• 关键词: Address; Adult; Aftercare; Age; Area; Benign; Biological Assay; Biological Markers; Blinded; CA-19-9 Antigen; Cancer Etiology; Cancer Patient; Cancer cell line; Clinic; Clinical; Clinical Trials; Coupled; Coupling; Cross-Sectional Studies; DNA; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Early Diagnosis; Early Intervention; Early treatment; Etiology; Evaluation; Excision; Failure; Future; Genetically Engineered Mouse; Glypican; Goals; Health; Histology; Human; IL8 gene; Image; Individual; Indolent; Intervention; KRAS2 gene; Lesion; Life; Longitudinal Studies; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Medical; Methods; Modality; Monitor; Mucinous; Mus; Mutation; Normal Cell; Oncogenic; Operative Surgical Procedures; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatitis; Papillary; Patients; Populations at Risk; Proteoglycan; RNA; Risk; ST13 gene; Sampling; Sensitivity and Specificity; Serum; Staging; Survival Rate; Symptoms; System; Testing; Translating; Validation; actionable mutation; associated symptom; base; cancer therapy; cost; cost effective; cost efficient; curative treatments; diagnostic biomarker; early detection biomarkers; effective therapy; exosome; follow-up; genetic analysis; improved; improved outcome; intraepithelial; minimally invasive; mouse model; neoplastic; non-invasive imaging; novel; novel therapeutics; outcome forecast; pancreatic cancer cells; pre-clinical; preclinical study; prevent; screening; specific biomarkers; tumor; tumor progression; validation studies

 DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is amongst the deadliest and fastest progressing cancers, with a 3 to 6 month expected survival that minimally improves with current therapies. Therefore, we are facing an urgent need for new strategies for effective therapies for this cancer. One reason for our failure to significantly impct patient survival is often due to late stage diagnosis of pancreas cancer. Early diagnosis based on clinical symptoms has been a challenge due to the symptom-free disease course until patients develop aggressive and invasive disease. Surgical and other interventions could have a significant impact on improving the outcome of this disease if pancreatic cancer is diagnosed at an early stage. Unfortunately, potentially life saving non-invasive, sensitive and specific early detection methods are currently not available. Our efforts in this area led to the discovery of glypican-1 (GPC1) as specific biomarker present on serum exosomes of patients with early and late stage pancreatic cancer. Performing blinded analysis of 100 microliters of serum from 197 patients with pancreatic cancer before surgical resection of tumors, 100 normal individuals and 26 patients with non-neoplastic diseases of the pancreas, we were able to detect GPC1+ exosomes with 100% specificity and sensitivity in patients with pancreas cancer, including 7 patients with precursor lesions (early pancreatic intraepithelial neoplastic (PanIN) and intraductal papillary mucinous neoplastic (IPMN) lesions). Importantly, serum assay for CA- 19-9 performed less effectively and could not distinguish between pancreatic lesions due to cancer and non-cancer etiology. Successful validation of putative serum biomarkers requires a thorough pre-clinical characterization to identify specific windows of utility and to explore the benefit of combining non-invasive imaging to increase efficacy. In this proposal, we will employ genetically engineered mouse models of PDAC to perform cross-sectional and longitudinal studies that couple histological grading of tumors, genetic analysis of exosomes derived DNA/RNA and non-invasive MRI with the goal of establishing the utility of GPC1+ serum exosomes for reliable early detection of pancreatic cancer. Additionally, such method could also allow for reliable monitoring of post treatment/follow-up disease assessment/burden. By coupling non-invasive MRI as a validation of GCP1+ serum exosomes-based detection of pancreatic cancer, we hope to identify an informative and clinically useful diagnostic system for early detection of pancreatic cancer. Such efforts may enable early and effective therapy options for our patients.

 描述（由申请人提供）：胰腺导管腺癌（PDAC）是最致命和进展最快的癌症之一，预期生存期为3至6个月，目前的治疗方法改善最小。因此，我们迫切需要新的策略来有效治疗这种癌症。我们未能显著影响患者生存的一个原因通常是由于胰腺癌的晚期诊断。基于临床症状的早期诊断一直是一个挑战，因为在患者发展为侵袭性和侵袭性疾病之前，没有疾病过程。如果胰腺癌在早期被诊断出来，手术和其他干预措施可能会对改善这种疾病的结果产生重大影响。不幸的是，目前还没有可能挽救生命的非侵入性、敏感和特异的早期检测方法。我们在这一领域的努力导致发现磷脂酰肌醇蛋白聚糖-1（GPC1）作为存在于早期和晚期胰腺癌患者血清外泌体上的特异性生物标志物。对来自197名手术切除肿瘤前的胰腺癌患者、100名正常个体和26名胰腺非肿瘤性疾病患者的100微升血清进行盲法分析，我们能够在胰腺癌患者中以100%特异性和灵敏度检测GPC 1+外泌体，包括7例前驱病变患者（早期胰腺上皮内瘤样病变（PanIN）和导管内乳头状粘液瘤样病变（IPMN））。重要的是，CA-19 - 9的血清测定的效果较差，并且不能区分由于癌症和非癌症病因引起的胰腺病变。推定的血清生物标志物的成功验证需要彻底的临床前表征，以确定特定的实用窗口，并探索结合非侵入性成像以提高疗效的益处。在该提案中，我们将采用PDAC的基因工程小鼠模型进行横断面和纵向研究，这些研究将肿瘤的组织学分级、外泌体衍生的DNA/RNA的遗传分析和非侵入性MRI结合起来，目的是建立GPC 1+血清外泌体用于胰腺癌可靠早期检测的效用。此外，这种方法还可以允许可靠地监测治疗后/随访疾病评估/负担。通过结合非侵入性MRI作为对基于GCP1+血清外泌体的胰腺癌检测的验证，我们希望确定一种用于胰腺癌早期检测的信息丰富且临床有用的诊断系统。这些努力可以为我们的患者提供早期和有效的治疗选择。