TMOD-04NOVEL ORTHOTOPIC XENOGRAFT MOUSE MODELS OF TWO PEDIATRIC METASTATIC INTRACRANIAL GERMINOMAS: MODEL DEVELOPMENT AND CHARACTERIZATION

Abstract

INTRODUCTION: Despite comprising up to 10% of pediatric CNS tumors, an animal model of intracranial germinoma has not been previously established. Standard of care for germinoma is radiation therapy, with recent evidence that neo-adjuvant chemotherapy may allow reduction of radiation dose, but concern for neuro-cognitive toxicity remains despite the reduction of radiation. A clinically relevant animal model of germinoma would facilitate investigation and discovery of novel agents which may obviate the need for radiation in the future. METHODS: To develop xenograft mouse models, we implanted germinoma tumor cells from two children with metastatic disease, one from a surgical specimen of a cervical metastatic tumor and the second from disseminated tumor cells in the CSF, directly into the right cerebral hemispheres of NOD-SCID mice. RESULTS: The germinoma tumors have been serially passaged in xenografts 5 times, with each passaged tumor maintaining the ability to generate tumors, suggestive of the persistence of viable tumorigenic/tumor stem cells. Both patient tumor samples have whole exome sequencing; one of the two models has a germinoma-associated mutation in kit. This mutation was confirmed by pyrosequencing and was maintained in all 5 xenograft tumor passages. In the kit wildtype model, kit was over-expressed as documented by IHC staining. Histopathologic staining demonstrated that both models maintain similarity with the original patient tumors. Cultured cells were grown as a monolayer from one model, and a cell line was established. CONCLUSIONS: Our orthotopic xenograft murine models of two metastatic pediatric germinomas are the first to be established for this tumor type. These models will allow much needed pre-clinical drug testing of chemotherapeutics and combination therapies as well as further biologic characterization of pediatric germinomas.