Abstract 4943: Orthotopic transplantation of pancreatic cancer PDX models increases murine stroma content, but does not influence therapeutic response to standard of care

Abstract

Abstract Background: Reasons for the poor prognosis of pancreatic cancer are advanced and inoperable tumor stages at time of diagnosis and resistance to conventional therapies. Patient-derived xenografts (PDX) represent a valuable tool for the prediction of therapy response, the identification of new biomarkers and therapeutic targets or pancreatic cancer specific activated pathways (MAPK, hedgehog). However, PDX tumors differ from patient tumors as their surrounding tissue is replaced by murine stroma within 3 to 9 weeks after primary transplantation. Since the desmoplastic stroma has an impact on the progression and treatment of pancreatic cancer, we investigated the characteristics and function of murine stroma components in PDX models of pancreatic ductal adenocarcinoma (PDAC). Methods: We analyzed the relevance of murine cancer-associated fibroblasts (CAFs) for therapeutic response by comparing orthotopic with s.c. transplantation in PDX. We selected a cohort of 3 PDAC PDX with different growth rates (slow, median and fast growth). Human pancreatic tumor material was implanted s.c. or orthotopically into immunodeficient mice. After successful engraftment, the chemosensitivity to standard of care (SoC) drugs (focus on 2 to 3 drugs) was determined according to clinically relevant and optimized schedules. Growth of orthotopic PDX models was monitored via high-resolution ultrasound. Cryo- and formalin-preserved tumor tissues from the chemosensitivity studies were collected and analyzed for specific stroma markers (collagen I and αSMA). Results: In general, the response profiles in our experiments have closely reflected patient’s response in the clinic for the drug combination gemcitabine and nab-paclitaxel. There were no differences in response when comparing s.c. with orthotopic growing tumors. Semi-quantitative analysis of tumor sections showed that orthotopic tumors contain more murine stroma compared to s.c. tumors. Comparison of treated and untreated tumors revealed a strong reduction of the tumor cell content by the SoC treatment, whereas CAFs (collagen I and αSMA positive fraction) were not affected. Conclusion: In summary, this study revealed that orthotopic transplantation results in the growth of tumors with an improved and functional tumor microenvironment. Therapy is effective on the pancreatic cancer cells, however, tumor stroma seems apparently to be inherent resistant towards conventional therapy. The remaining tumor stroma might provide a survival nice for some tumor cells - leading to the frequently observed disease relapse. Therefore, orthotopic PDX are considered to be the more clinical relevant models in comparison to s.c. PDX because they mimic closely the human pancreatic cancer microenvironment and also favor the development of metastasis. Further, targeting the tumor stroma should be implicated into clinical treatment strategies. Citation Format: Ulrike Pfohl, Diana Behrens, Iduna Fichtner, Jens Hoffmann, Britta Büttner, Wolfgang Walther. Orthotopic transplantation of pancreatic cancer PDX models increases murine stroma content, but does not influence therapeutic response to standard of care [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4943. doi:10.1158/1538-7445.AM2017-4943