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) 是最致命且进展最快的癌症之一，预计生存期为 3 至 6 个月，而目前的治疗方法只能勉强改善。因此，我们迫切需要寻找有效治疗这种癌症的新策略。我们未能显着影响患者生存的原因之一通常是由于胰腺癌的晚期诊断。由于患者在发展为侵袭性和侵袭性疾病之前无症状病程，因此基于临床症状的早期诊断一直是一个挑战。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、敏感且特异的早期检测方法。我们在这一领域的努力发现了磷脂酰肌醇蛋白聚糖-1 (GPC1) 作为早期和晚期胰腺癌患者血清外泌体中存在的特异性生物标志物。通过对 197 名胰腺癌手术切除前患者、100 名正常人和 26 名胰腺非肿瘤性疾病患者的 100 微升血清进行盲法分析，我们能够以 100% 的特异性和敏感性检测胰腺癌患者中的 GPC1+ 外泌体，其中包括 7 名有前驱病变（早期胰腺上皮内肿瘤）的患者。 （PanIN）和导管内乳头状粘液性肿瘤（IPMN）病变）。重要的是，CA-19-9 的血清测定效果较差，并且无法区分癌症和非癌症病因引起的胰腺病变。推定血清生物标志物的成功验证需要彻底的临床前表征，以确定特定的效用窗口，并探索结合非侵入性成像以提高疗效的好处。在本提案中，我们将采用 PDAC 基因工程小鼠模型进行横断面和纵向研究，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 GPC1+ 血清外泌体在胰腺癌可靠早期检测中的实用性。此外，这种方法还可以对治疗后/后续疾病评估/负担进行可靠监测。通过结合非侵入性 MRI 作为基于 GCP1+ 血清外泌体的胰腺癌检测的验证，我们希望找到一种信息丰富且临床有用的诊断系统，用于早期检测胰腺癌。这些努力可以为我们的患者提供早期有效的治疗选择。