HG-18: NOVEL OLIG2 INHIBITOR DEMONSTRATES PRE-CLINICAL EFFICACY IN PEDIATRIC GBM

BACKGROUND: Oligodendrocyte Lineage Transcription Factor 2 (OLIG2) is pro-mitotic and highly expressed in gliomas. We evaluated in vitro and in vivo efficacy of CT-179, an OLIG2 chemical inhibitor, alone and combined with radiation in pediatric glioblastoma (pGBM). METHODS: Cells from 8 patient tumor-derived orthotopic xenograft pGBM models with elevated OLIG2 expression were treated with CT-179 (0-10 µM) in both serum-based and serum-free media (favoring enrichment of tumor stem cells). Cell viability was measured 5 times over 2 weeks. Tumor cells were then exposed to varying doses of CT-179 (0-1 µM) and radiation (0-8 Gy). Inhibition of cell growth and colony-forming efficiency were determined with high-throughput imaging. Finally, 105 pGBM cells were orthotopically-implanted into mice. After 2 weeks, 4 weeks of treatment was initiated with vehicle, focal radiation (2 Gy/day, 5 days), CT-179 (15 mg/kg, gavage), or radiation plus CT-179. Drug concentration was examined in blood, normal brain, and tumor. RESULTS: CT-179 inhibited cell viability in both time- and dose-dependent manners in all 8 pGBM tumors in both media (IC50 0.03-10 µM). Radiation potentiated the effects of CT-179 at low to moderate drug doses (0.03-1 µM). In vivo treatment in one pGBM xenograft model has been completed. No animals died during treatment from drug-related toxicity. Survival analysis is ongoing. CONCLUSION: The OLIG2 inhibitor CT-179 demonstrated in vitro efficacy against numerous pGBM samples. CT-179 is well tolerated in vivo. Significant extension of animal survival is anticipated. Our data suggest that OLIG2 inhibition may be an effective strategy for future pGBM clinical trials.