Pancreatic adenocarcinoma secretome as a dynamic biomarker for patient stromal reprogramming efficacy

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PROJECT SUMMARY/ABSTRACT Pancreatic cancer is predicted to soon become the second leading cause of cancer deaths in the USA. For the few patients diagnosed early, surgery is the best option, yet surgery alone is rarely curative. Hence, preoperative chemotherapy plus radiotherapy have a potential of increasing the possibility for long-term survival. A unique hallmark of pancreatic cancer is “desmoplasia”; pancreatic cancer’s non-tumor cells expansion & fibrosis. Cancer cells modify the local neighborhood cells (i.e., desmoplasia or stroma) in a way that these promote, instead of normally restrict, tumor growth via specific cancer associated fibroblastic cells (CAFs). At the Fox Chase Cancer Center Marvin & Concetta Greenberg Pancreatic Cancer Institute, extensive prior work has established the key relationship between the pancreatic neighborhood, the neoadjuvant-generated local fibrosis, & patient survival. When the neighborhood cells (including CAFs, immune & other cells) are altered by the epithelial cells and/or by preoperative therapy, this local reaction may engage therapy resistance. Understanding this relationship is key in treating pancreatic cancer & effective therapy must be aimed at “normalization” of the neighborhood cells to return its natural tumor suppressive activity. What is poorly understood is the impact of the various paracrine mediators that act as the language between epithelial tumor cells, CAFs, immune cells, and other constituents of the tumor. Further, a gap in our knowledge exists for our understanding of which chemokines & cytokines are influenced by neoadjuvant therapy in pancreatic cancer. In this study we will determine the changes in tumor-neighborhood secretome signaling players associated with preoperative therapy. The study proposes to test the feasibility of monitoring the secretory changes subsequent to a new therapy intervention, implemented after chemo/radiation & before surgery, aimed to reprogram the stroma and its interactions. We will take advantage of the 4-6 week waiting period before surgery, as a “Window of Opportunity,” to test three microenvironment “normalizing” drugs (PHL: paricalcitol, hydroxychloroquine, & losartan) with demonstrated excellent tolerability for each in pancreatic cancer patients receiving chemotherapy. In this phase I trial, we will establish the feasibility for quantifying the effect of the total neoadjuvant therapy/PHL combination on the pancreas secretome as measured by inflammatory & proliferative chemokine & cytokines in pancreatic juice. Establishing a paradigm for “window of opportunity” sampling will allow us to assess our ability to influence the “neighborhood normalizing” hypothesis at the secretome level. Ultimately, this study will serve as a model to treat & monitor in real-time the efficacy for subsequent patients as well as to test new promising therapies in future pancreatic cancer “window of opportunity” trials.