MODL-29. Molecular Landscape of a comprehensive panel of pediatric brain cancer Patient-derived orthotopic xenograft (PDOX) models inform unique targets for drug responsiveness. (3rd June 2022)

• Record Type: Journal Article
• Authors: Braun, Frank K; Brabetz, Sebastian; Qi, Lin; Du, Yuchen; Kogiso, Mari; Zhang, Hui Yuan; Linday, Holly; Teo, Wanyee; Baxter, Patricia; Su, Jack M F; Adekunle, Adesina; Goeun, Bae; Powell, Reid T; Parsons, Donald W; Chintagumpala, Murali; Stephan, Clifford C; Pfister, Stefan; Lau, Ching C; Kool, Marcel; Li, Xiao-Nan
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 1
• Page Start: i175
• Page End: i175
• Publication Date: 2022-06-03
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac079.652
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Brain tumor is a leading cause of cancer related death in children. In addition to replicating histopathology, animal models faithfully replicating genetic/epigenetic abnormalities, molecular subtypes and broad inter-tumoral heterogeneities are needed. Through direct implantation of patient surgical or autopsied tumor tissues into matching locations in the brains of SCID mice, we developed a panel of 150 PDOX mouse models. Here, we report the analysis of 74 of the 150 PDOX models, 45 matching patient tissues and 60 non-tumorigenic samples to a well-annotated reference cohort of 2, 801 methylation profiles of primary brain tumors. Our data showed that the lack of tumorigenicity was neither correlated with molecular subtypes nor predicted by low cell viabilities of the patient samples. Methylation profiling identified PDOX models representing nearly a full spectrum of molecular subtypes of pediatric brain tumors including GBM, medulloblastoma, ependymoma and ATRT. Direct comparison with the original patient tumors confirmed the replication of molecular subtypes. ONCOplot [FB1] analysis of PDOX models derived from matching pairs of primary and recurrent tumors (n=8) revealed close clustering with the patient tumors. Investigation of metastatic properties was performed in 13 MB models by harvesting and sub-transplanting matching PDOX primary tumors in the cerebella and metastatic tumors in the spinal cords. To confirm the potential and power of PDOX models in preclinical drug testing, we applied fractionated radiation (2 Gy/day x 5 days) and optimized multi-agent combinatory chemotherapies in MB models of the four major subgroups. High-throughput combination drug screening with ~ 8, 000 drugs in PDOX-derived GBM cell lines and primary cultures of MB PDOX cells identified a library of ~ 3, 500 drugs that were active in pediatric brain tumors. In summary, this study provides detailed information on molecular subclassification of a uniquely large cohort of PDOX models to serve as essential tools for brain tumor research.