MODL-31. RADIATION-DERIVED TREATMENT-RESISTANT PDX AND CELL CULTURE MODELS RECAPITULATE THE CHARACTERISTICS OF MATCHED PRIMARY/RECURRENT PEDIATRIC HIGH-GRADE GLIOMA. (4th December 2020)

• Record Type: Journal Article
• Authors: Knox, Aaron J; Flannery, Patrick; Zukosky, Anjali; DeSisto, John; Sanford, Bridget; van Court, Benjamin; Donson, Andrew; Lemma, Rakeb; Chatwin, Hannah; Karam, Sana D; Vibhakar, Rajeev; Jones, Ken; Green, Adam L
• Is Part Of: Neuro-oncology. Volume 22(2020)Supplement 3
• Page Start: iii417
• Page End: iii417
• Publication Date: 2020-12-04
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noaa222.604
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Pediatric high-grade glioma (pHGG) is the most common cause of childhood cancer death. Recurrence after therapy is a major challenge, since recurrent pHGG proliferates aggressively and resists therapy. We developed and validated preclinical models of matched primary and recurrent tumors, providing a method to study recurrence and potential therapies. METHODS: We irradiated H3K27M thalamic pHGG cells (BT245) (8 Gy/week, 2Gy fractions x3 weeks) and propagated the surviving cells (BT245R). We developed a murine recurrence model by orthotopically implanting BT245 cells, irradiating the resultant tumors (4 Gy/day x2d) and propagating irradiated (BT245RM) or control (BT245CM) tumor cells at endpoint. We performed phenotypic analyses, RNA-Seq, and drug testing. RESULTS: BT245R cells were more stemlike than BT245, with an 8-fold greater rate of neurosphere formation (p<0.03). Geneset enrichment analysis showed similar molecular changes in BT245RM cells and primary/recurrent H3K27M pHGG patient sample pair, including relaxation of the G2/M cell cycle checkpoint (Hallmark_G2M_Checkpoint: BT245RM NES=-5.95, FDR=0.0; patient NES=-5.86, FDR=0.0), downregulation of MYC targets (Hallmark_MYC_Targets_V1: BT245RM NES=-7.43, FDR=0.0; patient NES=-5.86, FDR=0.0), and decreased differentiation (Go_Regulation_of_Stem_Cell_Differentiation: BT245RM NES=-3.35, FDR=0.0; patient NES=-3.15, FDR=0.0). Enrichment of the protein_kinase_C_signaling in BT245RM (NES=2.18, FDR=0.03) suggested response to MAPK pathway inhibition. BT245R cells were twice as sensitive as BT245 cells to the MEK inhibitor trametinib (p<0.05). CONCLUSIONS: Our neurosphere and murine orthotopic patient-derived xenograft models recapitulate gene expression changes of matched primary/recurrent pHGG. RNA-Seq analysis validated the model against patient samples and identified trametinib as potentially effective in recurrent pHGG.