Fusion gene mutations as biomarkers of pancreatic cancer lymph node metastases

Among the more common types of cancer, pancreatic cancer is the most deadly. Overall survival is not more than 5%. The only effective therapy is resection of the pancreas and surrounding tissues, and this radical procedure produces long term benefits in only 8-30% of the patients who undergo surgery. Moreover, almost 5% of patients who undergo radical resection of the pancreas die on the operating table. Due to the very high risk of surgical mortality, it is absolutely essential to develop better assays to identify those patients who will benefit from surgery. We know that patients in whom the cancer has spread to distant lymph nodes will not benefit. Unfortunately, our assays for detecting cancer cells in such lymph nodes are not sensitive enough or specific enough, and the majority of patients who undergo radical resection of the pancreas have undetected cancer in distant lymph node and undergo resection to no benefit. Our objective in this pilot project is to begin to develop new protocols for detecting the spread of pancreatic cancer. We have outstanding technology that enables us to obtain samples from lymph nodes using minimally invasive endoscopic techniques. What we lack are appropriate assays for the presence of tumor cells in those samples. Recently, our laboratory group has developed new RNA sequencing technology that enables us, for the first time, to detect the products of novel mutations that arise due to rearrangement of the genome of tumor cells. Such cells have defective gene repair machinery, and genes are often broken and repaired in ways that result in parts of one gene being fused to parts of another gene. These gene fusion mutations have the potential to generate novel, tumor-specific cancer genes that drive tumor formation. We can now detect these genes, which occur only in tumor cells, and are ideal markers for the presence of tumor cells in lymph nodes. Our objective in this pilot project is to identify the products of these fusion gene mutations in pancreatic cancer samples. We will then develop very sensitive assays for these fusion gene products and carry out a proof-of-concept screen to determine if these markers can be used to detect tumor cells in lymph node biopsies. Completion of these pilot experiments will provide the preliminary data that we will need to obtain the funds necessary to develop a clinical assay for the presence of pancreatic tumor cells in distant lymph nodes. This assay has the potential to spare a large number of patients the risk and expense of a radical surgical procedure that will be of no benefit if the cancer has already spread. In the process of developing this assay, we will also identify novel pancreatic cancer genes; and our hope is that some of these genes may be exploited as druggable targets for treatment of pancreatic cancer. Thus, our near term goals are to develop assays, but our long term goals are to develop treatments for this devastating disease.