The symptoms of pancreatic cancer are usually non-specific and late. Existing blood tumor biomarkers, such as carbohydrate antigen 19-9 (CA19-9), are not sensitive and specific enough to serve as useful screening tests. Tools for earlier detection could increase the proportion of patients who are diagnosed at early stages and potentially cured with surgical resection. Aptamers are oligonucleotide (RNA or DNA) molecules that directly bind to proteins with high specificity and can be used for the dual purpose of identifying novel biomarkers and detecting them in body fluids. We used a novel selection method (known as secretome selection) to identify aptamers that bind to proteins that are secreted by cultured pancreatic cancer cells but not to those secreted by non-cancerous pancreatic cells. One winning aptamer from this selection binds Cyclophilin B (CypB), a protein that has not previously been investigated as a blood biomarker for pancreatic cancer. We have demonstrated that CypB serum levels discriminate well between pancreatic cancer patients and healthy volunteers but not as well between patients with pancreatic cancer and patients with benign pancreatic disease. Our primary hypothesis is that a similar positive/negative aptamer selection strategy can be applied to serum samples from patients with pancreatic cancer and benign pancreatic disease to identify novel serum biomarkers that are specific for pancreatic cancer.
The specific aims of this project are: 1) To identify additional pancreatic cancer biomarkers using an aptamer selection strategy applied to blood samples from human patients. 2) To develop assays based on these selected aptamers (including the CypB aptamer) that could be used clinically for the detection of blood biomarkers. 3) To retrospectively evaluate whether these candidate biomarkers can distinguish between patients with early pancreatic cancer, patients with benign pancreatic diseases, and unaffected patients. The successful completion of this project will lead to the identification of new biomarkers that may be useful for the diagnosis, staging, and/or treatment of pancreatic cancer. Moreover, this approach to biomarker selection can be generalized to other cancers for which better biomarkers are needed.
Pancreatic cancer is the fourth leading cause of cancer deaths in this country (40,000 deaths per year), and greater than 90% of patients diagnosed with pancreatic cancer die from it. Pancreatic cancer tends to present at advanced stages because there is no effective screening test and presenting symptoms are often non- specific (e.g., weight loss, anorexia, indigestion). We have developed a strategy to identify biomarkers that are present in the blood of patients with pancreatic cancer but not benign pancreatic diseases. A non-invasive biomarker assay could be applied as a screening test to patients at high risk for pancreatic cancer (e.g., patients with chronic pancreatitis, diabetes mellitus, or a strong family history of pancreatic cancer) or as a diagnostic test in patients with non-specific symptoms. If we can detect more tumors at early stages, when they can be resected, we can increase the proportion of patients with pancreatic cancer who are cured.
| Naqvi, Ibtehaj; Gunaratne, Ruwan; McDade, Jessica E et al. (2018) Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis. Mol Ther 26:1020-1031 |
| Hesler, Rachel A; Huang, Jennifer J; Starr, Mark D et al. (2016) TGF-?-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3. Carcinogenesis 37:1041-1051 |
