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.
It is well recognized that pancreatic cancer has a dismal 5-year prognosis despite current treatment efforts and a dominant reason for this is the late stage diagnosis due to indolent clinical symptoms associated with early stages of pancreatic cancer. It is generally accepted that early intervention via surgery could significantly improve survival of our patients, unfortunately reliable diagnostic modalities are lacking at the moment. This application addresses this unmet medical need and proposes the use mouse models to test an exosomes-based diagnostic marker to detect early stage pancreatic cancer, and when combined with MRI imaging it may offer an early detection system that will aid in the development of effective therapies.
| Mendt, Mayela; Kamerkar, Sushrut; Sugimoto, Hikaru et al. (2018) Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 3: |
| Kalluri, Raghu (2016) The biology and function of exosomes in cancer. J Clin Invest 126:1208-15 |
