Molecular Profiling of Pancreatic Cancer

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One of the major challenges in pancreatic cancer research is the availability of clinical samples from patients undergoing surgical resection with complete demographic and clinico-pathological information. Our primary source of clinical samples is through the NCI-University of Maryland Resource Contract of the Laboratory of Human Carcinogenesis. In addition, through our collaboration around the world, we are establishing an International Consortium of pancreatic cancer cohorts to be used in our studies. This collection will be an invaluable asset for our pancreatic cancer studies. Using a global strategy, pancreatic ductal adenocarcinoma (PDAC) samples were analyzed by mRNA and miRNA expression, and metabolite profiling. Analysis of mRNA and miRNA expression profile identified genes that are associated with patients outcome and may contribute to disease aggressiveness and resistance to available therapy. These candidate genes are further validated in independent cohorts of PDAC and their mechanistic role in tumor progression and chemoresistance has been examined. Briefly, we found that a lower expression of DPEP1 (dipeptidase 1) in tumor was associated with poor survival in two independent cohorts of surgically resected patients and was independent of stage and resection margin status. DPEP1 expression was significantly lower in tumors as compared to non-tumor pancreas from the same patient in both the cohorts. Overexpression of DPEP1 in pancreatic cancer cell line Panc1 inhibited cell migration and invasion, and increased the sensitivity to gemcitabine, a first-line drug for treating pancreatic cancer. In view of these findings, we propose that DPEP1 may be a useful target in designing an improved therapeutic strategy. These findings are being submitted for publication. We are currently analyzing mRNA and miRNA expression profiling and metabolomics data to identify molecular subtypes of PDAC, which dictates patients outcome. To move towards our second goal of this project, we are continuing our efforts of finalizing a protocol and questionnaire to initiate a case-control study of pancreatic cancer in the greater Baltimore area with myself as the Principal Investigator. Our concept proposal for the case-control study has been earlier reviewed by the NCI, Medical Oncology Branch Scientific Review Committee. Although committee acknowledged that the proposed study is very important to address the current unmet clinical needs of early detection and effective treatment in PDAC, the approval is deferred with stipulations and recommendations. The proposal is being revised for resubmission.