A major challenge for the successful development and application of targeted therapies for pancreas cancer is the absence of predictive markers which would assist in patient selection for new clinical trials. Since these novel, cancer biology-based therapeutics are designed to block highly specific pathways which may or may not be active or essential in any given patient's tumor, many patients currently enter clinical trials in which they have little chance of receiving benefit, and importantly, lose valuable time in which to try alternative approaches that could have been more beneficial. However, being able to determine markers which could better predict a given patients chances for success with a given therapy is still extremely problematic and requires access to patient tumor material before, during and after treatment in order to compare the molecular basis of response. Our laboratory is utilizing the growth of patient-derived surgical specimens of pancreatic tumors in SCID mice as a model for evaluating the efficacy of new targeted therapies for pancreatic cancer and as a source of material with which to analyze the basis of the observed sensitivity or resistance. The overall goal of our ongoing research is to obtain a clear understanding of the degree to which sensitivity vs. resistance to novel therapies occurs in patient tumors and to identify both markers for sensitivity vs. resistance as well as strategies for overcoming resistance. One therapeutic that we are currently evaluating is Apo2L/TRAIL, an apoptosis inducing death ligand of the TNF family for which there is considerable pre-clinical (and now clinical) optimism. Our data show for the first time that many patients' pancreatic tumors grown in the SCID mouse/xenograft model are highly sensitive to Apo2L/ TRAIL. However, other patients' tumors are resistant and thus we predict that certain patients may not benefit from this therapy. We are currently developing a panel of patients' pancreas tumors for which we have determined the sensitivity or resistance to Apo2L/TRAIL and are comparing the expression levels of proteins that are either critical components of apoptotic signaling pathways or implicated as inhibitors of this signaling. This analysis is currently being carried out by western blot analysis and immunohistochemistry. In this R03 application, we are requesting funding to carry out the first differential gene expression analysis of these same invaluable patient-derived samples in order to 1) clarify the basis for differences in protein expression and 2) to identify novel genes or patterns of gene expression related to sensitivity or resistance of these tumors to Apo2L/TRAIL that could be used as markers for selecting patients who have the best chance of benefiting from this new and exciting targeted therapy. Since we already have the samples of characterized tumors, this research could have an immediate positive impact on the ability of patients with pancreatic cancer to choose the clinical trial in which they have greatest chance for success. ? ? ?
