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（由适用提供）：胰腺导管腺癌（PDAC）是最致命，进展最快的癌症之一，预计3到6个月的预期生存率可以通过当前的治疗方法来最小。因此，我们迫切需要采取新的策略来治疗该癌症。我们未能显着影响患者生存的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因无症状疾病病程而一直是一个挑战，直到患者出现侵略性和侵入性疾病为止。如果在早期诊断出胰腺癌，手术和其他干预措施可能会对改善该疾病的结果产生重大影响。不幸的是，目前尚无生命挽救无创，敏感和特定的早期检测方法。我们在这一领域的努力导致在早期和晚期胰腺癌患者的血清外泌体中发现了聚糖-1（GPC1）作为特定的生物标志物。 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）和导管内乳头状粘液肿瘤（IPMN）病变。重要的是，CA-19-9的血清测定效果较差，无法区分由于癌症和非癌症病因引起的胰腺病变。成功验证推定的血清生物标志物需要彻底的临床前表征，以识别特定的效用窗口，并探索结合非侵入性成像以提高效率的好处。在该提案中，我们将采用PDAC的基因工程小鼠模型进行横截面和纵向研究，这些研究对肿瘤进行组织学分级，对衍生的DNA/RNA的遗传分析和非侵入性MRI的遗传分析，目的是确定GPC1+血清外os体的实用性，以便于可靠的早期检测pancection pancreatic癌症。此外，这种方法还可以可靠地监测治疗/随访疾病评估/负担。通过将非侵入性MRI耦合作为基于GCP1+血清外泌体的胰腺癌检测的验证，我们希望确定一种信息性且具有临床上有用的诊断系统，以便早期检测胰腺癌。这样的努力可能可以为我们的患者提供早期有效的治疗选择。