Histopathological Tumor and Normal Tissue Responses after 3D-Planned Arc Radiotherapy in an Orthotopic Xenograft Mouse Model of Human Pancreatic Cancer

SIMPLE SUMMARY: Despite intense research, the prognosis of patients with pancreatic cancer remains very poor without significant improvements over the past years. Novel therapeutic approaches may contribute to overcome therapeutic resistance and improve clinical outcome. Recently, small-animal imaging and high-precision irradiation devices for preclinical tumor models have been developed. The present preclinical study aimed to assess the accuracy of small-animal imaging and high-precision radiotherapy (RT) in an orthotopic xenograft pancreatic tumor mouse model by histopathological examination of the DNA damage marker γH2AX. Immunohistochemical staining of the pancreatic tumor and abdominal organs confirmed the accuracy of outlining based on CBCT imaging as well as the subsequent stereotactic RT. A clinical example from a patient with pancreatic cancer demonstrates the translational nature of this study. Longitudinal follow-up after high-precision RT showed a significant survival benefit in comparison to untreated tumor-bearing control mice. This preclinical RT platform provides the ability to mimic contemporary human RT closely and to evaluate novel RT concepts for pancreas cancer treatment. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. Innovative treatment concepts may enhance oncological outcome. Clinically relevant tumor models are essential in developing new therapeutic strategies. In the present study, we used two human PDAC cell lines for an orthotopic xenograft mouse model and compared treatment characteristics between this in vivo tumor model and PDAC patients. Tumor-bearing mice received stereotactic high-precision irradiation using arc technique after 3D-treatment planning. Induction of DNA damage in tumors and organs at risk (OARs) was histopathologically analyzed by the DNA damage marker γH2AX and compared with results after unprecise whole-abdomen irradiation. Our mouse model and preclinical setup reflect the characteristics of PDAC patients and clinical RT. It was feasible to perform stereotactic high-precision RT after defining tumor and OARs by CT imaging. After stereotactic RT, a high rate of DNA damage was mainly observed in the tumor but not in OARs. The calculated dose distributions and the extent of the irradiation field correlate with histopathological staining and the clinical example. We established and validated 3D-planned stereotactic RT in an orthotopic PDAC mouse model, which reflects the human RT. The efficacy of the whole workflow of imaging, treatment planning, and high-precision RT was proven by longitudinal analysis showing a significant improved survival. Importantly, this model can be used to analyze tumor regression and therapy-related toxicity in one model and will allow drawing clinically relevant conclusions.