Patient-Derived Tumor Xenografts As Pharmacological Model Of Human Pancreatic Ductal Adenocarcinoma

Abstract INTRODUCTION and AIM Pancreatic ductal adenocarcinoma is a lethal disease with an overall survival rate of 5% and a median survival time of less than 6 months. Current systemic treatments offer only a modest benefit in symptom control and survival, thus surgery remains the most effective treatment. The exploitation of new therapeutics is an urgent need, but the research is braked by the limited value of the current preclinical models as predictors of patients response. The aim of our study is to develop patient-derived primary pancreatic ductal adenocarcinoma xenografts (PDAC-PDX) growing into the pancreas of recipient mice that retain features of the patient’s tumors and mimic the biological heterogeneity of human pancreatic cancer. METHODS Cancer specimens from patients undergoing cephalic duodenopancreatectomy were transplanted in NSG mice and orthotopically propagated by their re-implantation into the pancreas of SCID mice. Tumor burden was measured by abdominal palpation and by non invasive magnetic resonance imaging (MRI). PDAC-PDXs were characterized histologically, for mutational status (KRAS, TP53 and SMAD4), and responsiveness to gemcitabine. Gemcitabine was administered alone or combined with nab-paclitaxel, to mice bearing tumor in their pancreas; drugs were given intravenously on days 1 and 8 of each 21-day cycle to copy as much as possible patient’s recommendations. To determine the antitumor effects of the treatments, changes in tumor growth over time were evaluated by MRI and plasma level of Ca19-9. RESULTS Surgically resectable pancreatic adenocarcinoma (histologically confirmed) engrafted successfully in 5 cases (out of 11) and retained the molecular, morphological and biological features of the original patient tumors. Mutational landscape of the PDAC-PDXs reflect the clinical scenario: 80% are mutated in KRAS (G12D, G12R), 80% carry a TP53 mutation (I162F, R213*, Y220C, R248Q) and 20% show the deletion of SMAD4. Histological features recapitulate the human disease, the PDAC-PDXs exhibit a robust amount of host derived stroma with collagen deposition, constant through generations (up to five). Orthotopic growing PDAC-PDXs were marginal responsive to gemcitabine treatment, while significant response (stable disease and regression) was observed with the gemcitabine and nab-paclitaxel combination regimen, which was more efficacious than paclitaxel (equimolar dose). CONCLUSION PDAC-PDXs growing orthotopically in the pancreas of mice provide a valuable tool for the preclinical exploitation of novel therapeutics for pancreatic cancer. . Supported by Associazione Italiana per la Ricerca sul Cancro (AIRC 5 per mille n. 12182) and Fondazione “Eugenio Morandi” ONLUS per lo studio e la cura dei tumori del pancreas. Citation Format: Alessia Anastasia, Andrea Resovi, Carmen Ghilardi, Roberta Avigni, Edoardo Micotti, Lucia Minoli, Eugenio Scanziani, Carlo Corbellini, Eugenio Morandi, Dorina Belotti, Raffaella Giavazzi, MariaRosa Bani. Patient-derived tumor xenografts as pharmacological model of human pancreatic ductal adenocarcinoma [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 3857. doi:10.1158/1538-7445.AM2017-3857