Endogenous Mouse Models Of Pancreatic Adenocarcinoma As A Preclinical Trial Platform Characterized By Multiparametric Magnetic Resonance Imaging

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 MRI. Ptf1a +/Cre mice were crossed to Kras +/LSL-G12D (K)Tgfα(T), K;p53(P) +/fl , K;P fl/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;P fl/fl mice were injected twice a week with 120 mg/kg body weight with gemcitabine or 0.9% NaCl solution. MRI data were correlated with survival analysis, vascular staining, and histopathology of tumor specimens. Volume analysis was performed using semiautomatic segmentation of solid and cystic compartments. K ; P fl/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;P fl/fl mice. The final tumor volume ranged between 800 and 4500 mm 3 . Characterization of solid tumor tissue composition by DWI correlated well (R=72%) with the histopathology. K;P fl/fl , K;P +/R172H ; T, K;P +/fl ; T, and K; T models mostly developed highly fibrotic, well-differentiated PDAC (apparent diffusion coefficient, ADC=1.03-1.14), whereas cancers observed in K;P fl/+ animals revealed an anaplastic phenotype with significantly lower ADC values (0.8843 ± 0.05056). Spontaneous necrosis was detectable by DWI and DCE analysis. Intraductal mucinous papillary neoplasms (mIPMN) appeared hypointense on T2w MRI and were better perfused compared to hyperintense PDAC. Interestingly, the calculated ADC values of mIPMN lesions were similar to those of solid tumors (1.03 ± 0.012). Gemcitabine-treated K;P fl/fl animals showed an increased overall survival as well as tumor volume reduction in individual cases. Although selected animals revealed changes in tumor perfusion, no differences in tissue composition, reflected by the ADC values and histology, were noticed in vehicle- or gemcitabine-treated animals. In summary, based on tumor incidence, growth kinetic and overall survival criteria, we propose two very suitable models for preclinical therapy studies: K;P fl/fl and K;P +/fl ; T. The validated multimodal MRI-based methods are feasible for correct interpretation of spontaneous and drug-induced changes in tumor physiology when conducting preclinical therapy studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C8.