Abstract LB-328: Influence of radiation on the evolution of orthotopic xenografts initiated from glioblastoma stem-like cells

Abstract

Abstract Glioblastoma (GBM) is the most common and malignant primary adult brain cancer with a median survival of 15 months despite treatment with surgical resection followed by chemo-radiotherapy. By examining changes that occur following irradiation of brain tumor xenografts initiated from glioma stem-like cells (GSCs), this study seeks to better understand the impact of radiotherapy on GBM evolution. Therefore, we intracranially implanted CD133+ NSC11 cells, a well-documented GSC line, into nude mice. After 21 days, bioluminescence imaging was performed to confirm the presence of tumor prior to randomization into control and radiation therapy groups (3x5Gy). Following treatment, brain samples were collected at various time points out to morbidity to investigate changes in tumor morphology and histology. Further, tumors from morbid mice (control and 3x5Gy) were collected for viral integration site analysis (VISA). Initial survival analysis demonstrated a significant survival advantage for mice undergoing radiation therapy (+34.2 days) compared to controls. On gross examination of morphology at morbidity, brains bearing irradiated tumors contained tumor tissue that was softer, more adherent to the skull, and more likely to efface olfactory bulb(s) than control tumor brains. H&E staining demonstrated that irradiated tumors were more dense/compact and did not grow as infiltrative as tumors from control mice. These histological changes were followed up with VISA to determine whether certain clones were responsible for this difference. VISA revealed that irradiated tumors were heterogeneously enriched for clones with different integration sites when compared to control tumors and in vitro tumor lines. Heat map analysis of the number of clones present in each sample demonstrated that control tumors harbor fewer clones than in vitro lines and that radiated tumors harbor the fewest clones of all. Initial data also revealed that various doses of radiation (3x5Gy or 10x5Gy) can provide very similar selection pressures to limit the number of clones. Our results demonstrate that radiation, a treatment component for almost all glioblastoma patients, can have wide-ranging effects on the evolution of this dynamic tumor. In particular, the pressures imposed by radiation treatment seem to lead to the selection of a reduced number of clones. This selection may have future implications for tumor evolution and the treatment of recurrent GBM. Citation Format: Joseph H. McAbee, Barbara H. Rath, Kevin A. Camphausen, Philip J. Tofilon. Influence of radiation on the evolution of orthotopic xenografts initiated from glioblastoma stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-328.