ENDOGENOUS MOUSE MODELS OF PANCREATIC ADENOCARCINOMA AS A PRECLINICAL TRIAL PLATFORM CHARACTERIZED BY MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING
Heid I, Trajkovic-Arsic M, Gretzinger M,Kosanke Y,Steingoetter A, S. Sayyed Noel, P, B. Haller, Rummeny EJ , Schmid RM, Siveke JT and Braren R. (01-05-2011).
Research Area C
Development of strategies for early tumor detection and evaluation of new therapies in preclinical models is one of the main goals of current cancer research. Pancreatic Ductal Adenocarcinoma (PDAC) is a lethal disease, with no effective treatment plan. PDAC progression can be very well mimicked by established genetically engineered mouse models (GEMMs), representing an excellent platform for preclinical studies. Therefore tumor physiology, including growth kinetics, tumor perfusion and tumor composition, were characterized in several GEMM. In addition tumor response to the Standard therapeutic agent Gemcitabine was monitored by multiparametric magnetic resonance imaging (MRI). Ptf1a+/Cre mice were crossed to Kras+/LSL-G12D(K)Tgfα(T), K;p53(P)+/fl, K;Pfl/fl, K;P+/R172H;T and K;P+/fl;T GEMMs to generate conditional endogenous PDAC models. Animals were subjected to serial T2-weighted (T2w) MRI from 4-6 weeks of age onwards using 1,5 T clinical Scanner. Upon detection of solid tumor, longitudinal diffusion-weighted imaging (DWI) and dynamic contrast enhanced-MRI (DCE-MRI with Gd-DTPA) protocols were applied. For the evaluation of therapy response monitoring, K;Pfl/fl mice were injected twice a week with 120 mg/kg body weight with Gemcitabine or 0,9% NaCI solution. MRI data were correlated with survival analysis, vascular staining and histopathology of tumor specimens. Volume analysis was performed using semi-automatic segmentation of solid and cystic compartments. K;Pfl/fl, and K;P+/fl;T models showed 100% tumor incidence, detected by MRI and verified by histology. Moreover, K;P+/fl;T animals often presented with metastatic disease to lung and liver, easily identified on T2w scans, while no metastases were observed in K;Pfl/fl mice. The final tumor volume ranged between 800 and 4500