Preclinical Development of Targeted Stereotactic Body Radiation Therapy for Pancreatic Cancer

Abstract

Radiotherapy is a component of curative treatment for many tumors but treatment of pancreatic cancers is challenging due to their close proximity to adjacent dose limiting organs. It is predicted that stereotactic body radiotherapy (SBRT), that delivers a small number of higher-dose, highly conformal fractions to the tumor, will improve patient quality of life by improving local control and shortening treatment time. One goal of this project was to develop an orthotopic model of pancreas cancer (OCIP) as a clinically relevant platform for testing the ability of SBRT plus targeted agents such as MK-1775, a G2 checkpoint inhibitor, to improve local disease control, while sparing normal tissues, thereby improving the therapeutic ratio. OCIP xenografts were established from pancreatectomy specimens, and grown orthotopically in the pancreas of NRG mice. The OCIP23 model was used for the current study. It has mutations involving KRAS and p53, and a high level of hypoxia. For precise localization of the tumors in the abdomen, anesthetized mice were imaged with 7TMRI. Tumor volume was calculated by 3D segmentation using post-treatment MRI scans. For irradiation (delivered using an X-Rad C225Cx small animal irradiator) the mice were transferred from the MRI and re-imaged (CBCT) on the irradiator, and the images were registered and for guiding the radiation treatment. Radiation treatment commenced when the tumor size reached ∼6mm. Mice were treated with 5 fractions on a Mon/Wed/Fri schedule, using either 7 or 9 Gy per fraction delivered using a 180° arc and a 8mm field size. MK-1775 was given by oral gavage 24hrs after each SBRT fraction. The effect of MK-1775 inhibitor was examined on the response of various normal tissues to radiation given immediately pre- and post-treatment. A dose of 9 Gy x 5 fractions is close to the maximum tolerated by adjacent host tissues, but it fails to achieve cure in the preclinical model even with the addition of MK-1775. Treatment resulted in an initial reduction in size but regrowth occurred in all mice by 6-7 weeks post-treatment. Histological analysis at time of sacrifice of the mice showed no obvious damage to the intestine of the mice but some damage was observed in the left kidney. In addition, higher levels of crypt cell survival (acute) and reduced damage in the deeper tissue layers of the colorectal junction (late effects) were observed in mice given MK-1775 treatment suggesting some protection. We have developed a relevant preclinical platform to test approaches for improving the response of pancreatic cancers to SBRT when combined with novel agents such as MK-1775. Further studies are planned using hypoxia targeted agents.