B. Giri1, V. Sethi1, B. Garg1, A. Farrantella1, S. Kurtom1, S. Modi1, Z. Malchiodi1, L. Hellmund1, S. Ramakrishnan1, S. Banerjee1, A. Saluja1, S. Lavania1, V. Dudeja1 1University Of Miami,Department Of Surgery,Miami, FL, USA
Introduction: Most patients with localized pancreatic ductal cancer (PDAC), even after tumor resection and systemic chemotherapy, succumb to disease recurrence. Current animal models for PDAC do not recapitulate the patterns of disease recurrence following resection of primary tumor. The aim of the current study was to study recurrence and evaluate therapeutic strategies in an immunocompetent, clinically relevant model of PDAC resection.
Methods: Cancer cells derived from tumors arising in KPC (KrasLSL.G12D/+; p53R172H/+; PdxCretg/+) mice were co-injected with stromal cells (Pancreatic stellate cells from C57/B6 wild type mice) into the pancreas of immunocompetent mice to simulate the stroma rich tumor seen in human PDAC. Tumors were allowed to grow, resected 10-20 days later (after excluding metastatic disease) and animals were serially followed for tumor recurrence. Therapy with Gemcitabine (200mg/kg/week) and Paclitaxel (25 mg/kg/week) was used as a model to study the effect of adjuvant therapy in animals who underwent tumor resection.
Results: Similar to that seen in human disease, tumors formed after co-injection of KPC cells and stromal cells had a dense desmoplastic reaction. Resection of primary tumors at 20 days after implantation revealed uniform tumor volumes and microscopic examination of resected tumors showed negative margins indicating R0 resection. Resembling human PDAC, most animals developed intra-abdominal recurrence on follow up. Furthermore, when tumors were resected at 20 days, these animals showed improved overall survival (Median survival: 54.7) compared to mice that did not undergo resection (Median survival: 47). There was an even greater improvement in overall survival in mice which underwent adjuvant chemotherapy (Median survival: 71.5) demonstrating usefulness of this model in studying clinically relevant scenarios.
Conclusion: We describe a novel immunocompetent animal model that recapitulates human disease in morphology and recurrence patterns. We show that it can be used to evaluate therapy in clinical scenarios and may help characterize factors responsible for disease recurrence.
