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.