HGG-38. DEVELOPMENT AND COMPREHENSIVE CHARACTERIZATION AND UTILIZATION OF PRECLINICAL MODELS OF PEDIATRIC HIGH GRADE GLIOMAS

Midline high-grade gliomas (HGGs) are amongst the most challenging childhood cancers to treat. Recent advances in understanding the molecular drivers of these tumors have resulted from donated autopy or biopsy specimens. We have initiated a midline glioma preclinical initiative for producing in vitro and in vivo models that have well defined genomic profiles. We obtained 22 autopsy, 11 upfront biopsy (PNOC NCT 2274987) and 2 surgical resection samples. Collectively, specimens represented DIPGs (n=30) and thalamic HGGs (n=5). Single cell suspensions were generated for neurosphere culture and intracranial injection into mice. Specimens were considered viable if they resulted in two consecutive generations of murine tumor models or five in vitro passages. A total of 14 cell lines representing DIPG and thalamic glioma were generated and validated by short tandem repeat (STR) analysis. Orthotopic injections into non scid gamma (NSG) mice resulted in tumor formation (n=14) with molecular characteristics similar to the corresponding patient tumor. Eleven mouse implantations are still being monitored. In vivo models were validated by immunohistochemical staining for human mitochondria and H3K27M. Methylation and whole genome analysis of preclinical models were generated to assess similarities/shared pathways with human disease. In vitro and in vivo response to therapeutics including panobinostat and TAK228 was also assessed. A microdialysis procedure was optimized to assess blood brain barrier penetration of systemically administered therapeutics. Direct drug delivery was also evaluated using subcutaneously placed osmotic pumps with optimization of delivery rates, cannula depth and placement.