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.