DISP-16. RACIAL/ETHNIC DIFFERENCES OF PEDIATRIC BRAIN TUMORS IN PATIENT DERIVED ORTHOTOPIC XENOGRAFT (PDOX) MODEL DEVELOPMENT AND DRUG RESPONSES DETECTED BY HIGH-THROUGHPUT DRUG SCREENING

Abstract

Abstract Brain tumors are the leading cause of cancer-related death in children. While the last decade has ushered in significant advances in molecular subtyping of pediatric brain tumors, little is known about the biological differences among racial/ethnic populations. We previously completed high-throughput Screening (HTS) in 12 malignant glioma and 13 medulloblastoma models. For each model, cultured xenograft cells (primary or cell line) were maintained both as a classic monolayer and as 3D neurospheres then treated for 3-7 days with a library of ~8,000 drugs/investigational agents, each at 4 different doses (0.01~ 10 µM). The antitumor activities were evaluated by the level of suppressed cell proliferation that was determined by the area under the curve (AUC) for which our cutoff value was set at 0.75. In the current study, we performed a retrospective analysis to determine the race/ethnicity of these completed PDOX models. Our cohort of medulloblastoma models included 3 models from children who self-identified as Hispanic and 5 models from children who self-identified as, that allowed for a statistical analysis (t-test) to compare the differences between these two racial/ethnic groups. From the 8,000 drugs, we identified 11 drugs (mostly NSC compounds) that were equally active in both Hispanic and White children (i.e. commonly shared drugs), and 442 drugs that showed significantly different (P< 0.05) activities between the Hispanic and the White medulloblastomas grown as neurospheres and treated for 7 days. The difference of active drugs (AUC >0.75) was even more prominent. Compared with 38 active drugs in White children (i.e., privately active drugs, including Bortezomib, YM155, Carfilzomib, Daporinad, GMX-1778, Dalanzomib, Cucurbitacin, Bafilomycin, Vincristin and Mitoxantrone), the number was 0 for Hispanic children. Our data indicates a significant difference in drug response across different racial/ethnic groups and provides a strong rationale for additional examination of those differences with broader coverage of tumors.