MNGO-16ESTABLISHMENT OF A PATIENT - DERIVED ORTHOTOPIC MALIGNANT MENINGIOMA MODEL FOR THE DEVELOPMENT OF TARGETED THERAPY

Abstract

The majority of meningiomas are benign (WHO Grade I) and can be cured by surgery alone. However, 20% are non-benign meningioma (NBM) including atypical (Grade II) and malignant meningioma (Grade III), and pose a clinical problem due to their high recurrence rates after treatment. Preclinical development of novel therapeutics requires disease model that is representative of human NBM. However, patient-derived tumor models that recapitulate the genotype and phenotype of NBM are lacking. We established an orthotopic xenograft model from a patient with recurrent malignant meningioma that is based on tumor-sphere culture. Subdural implantation of the cultured cells in SCID mice reproducibly generated meningiomas that are lethal within 3 months, and excised tumors were serially transplantable for at least 7 generations. Pathological analysis of xenografts showed hypercellularity with whorl formations, and exhibited frequent mitotic figures, high proliferation index (Ki67 labeling 25%) and invasion to the brain parenchyma, hallmarks of malignant meningioma. The patient tumor, xenografts and cultured cells had strong expression of vimentin, a mesenchymal marker. Western blot analysis revealed that the original tumor and xenografts are NF2 (Merlin) negative, and sequencing verified NF2 mutation. This novel tumor model set a stage for us to test targeted and biological therapeutics for NBM. Our preliminary investigations in vitro include the use of dual PI3K and mTOR inhibitors, focal adhesion kinase (FAK) inhibitor, and oncolytic herpes simplex virus (oHSVs) (G47Δ and MG18L). MTS cell viability assay showed PI3K and mTOR inhibitors and oHSVs efficiently killed the tumor cells, while FAK inhibitor was ineffective. Thus our novel patient-derived orthotopic NBM model has NF2 deletion, faithfully recapitulates the human disease, and is reproducible and lethal. This model provides us with superb opportunities to develop much needed targeted therapeutics for treatment-refractory NBM, and currently studies examining oHSV efficacy in orthotopic tumor model are ongoing.