# title
PDTM-31. IDENTIFICATION OF PERSONALIZED ACTIVE AGENTS IN PEDIATRIC GLIOMAS THROUGH HIGH-THROUGHPUT DRUG SCREENING IN MATCHING PAIRS OF PATIENT DERIVED ORTHOTOPIC XENOGRAFT (PDOX) NEUROSPHERE AND MONOLAYER CELLS

# abstract
Glioblastoma (GBM) is one of the deadliest brain tumors both in adults and children. The efficacy of targeting mutated genes/pathways has not been systematically analyzed. Matching pairs of neurosphere and monolayer cell cultures from 4 molecularly characterized PDOX mouse models established from distinct clinical stages of pediatric glioma were treated with 7,913 drugs (mostly in clinical use or trials) at 4 doses (0-10 uM) for 3 and 7 days. Relatively long-term treatment was achieved for drug screening in most of the 4,629 compounds that were active in at least one culture at one time point. When gene mutations were druggable, not all inhibitors of the same family were active. In IC-4687GBM (a treatment-nave GBM), high NF1 mutation (>76-99% allele) frequency was found in patient tumor, xenografts, and cultured cells, but only 3/17 MEK inhibitors were active in neurospheres and 2/17 in monolayer cells on day 7. In IC-R0315GBM (from an autopsied terminal GBM) that carried PI3KCA mutation (allele frequency 22-27%), 5/33 PI3K inhibitors were active in neurospheres and 8/33 in monolayer cells after 7 days. In IC-3752GBM (recurrent GBM) and ICb-1227AA (radiation-induced anaplastic astrocytoma), no druggable mutations were detected. The number of active drugs on day 7 was 366 in IC-4768GBM, 406 in IC-3752GBM, 284 in IC-R0315GBM, and 305 in ICb-1227AA. When the 4 matching pairs of neurospheres and monolayers were compared, the agents active in both cultures ranged from 36% to 60%, active only in neurosphere from 10.3% to 25%, and active only in monolayer cells from 14.8% to 53%. We showed that long-term treatment is feasible for high-throughput drug screening. Targeting druggable mutations can be achieved. Neurospheres and monolayer cells do not always respond equally toward the same drugs, and effective targeting of both subpopulations is needed to generate prolonged animal survival times.

# authors[].organizations[].label
Texas A&M University Naresh K. Vashisht College of Medicine

# authors[].organizations[].label
Texas A&M University Naresh K. Vashisht College of Medicine

# authors[].organizations[].label
Center for Translational Cancer Research