Targeting Pediatric Glioblastomas by Combining OLIG2 Inhibitor CT-179 with Fractionated Radiation in a Panel of Patient-Derived Orthotopic Xenograft Mouse Models.

Abstract

The poor clinical outcomes of pediatric high-grade glioma (pHGG) highlight the urgent need for new therapies. Oligodendrocyte lineage transcription factor 2 () is a pro-mitotic transcription factor highly expressed in glioma stem cells and may represent a novel therapeutic target. To evaluate the therapeutic efficacy of aninhibitor CT-179 in pHGG, we determined themRNA expression in 10 patient-derived orthotopic xenograft (PDOX) models. In vitro activities of CT-179 were analyzed in monolayer and neurosphere cells (0-10 µM) with and without radiation (XRT) (0-8 Gy), brain penetration was evaluated in tumor-bearing PDOX mice, and in vivo efficacy was determined at 15-240 mg/kg (oral) alone or combined with XRT (2 Gy/day × 5 days). Changes in animal survival times were analyzed using the Kaplan-Meier method, followed by pair-wise comparisons. IncreasedmRNA expression was detected in seven out of ten PDOX models. CT-179 inhibited cell viability in a time- and dose-dependent manner in all eight pGBM xenograft tumors (IC0.03-10 µM) and was potentiated by XRT (0.03-1 µM). Oral gavage (24 mg/kg) of CT-179 for 5 days led to effective penetration in mouse cerebrum (3232.7 ± 569.2 ng/g), cerebellum (1563.3 ± 269.6 ng/g), brain stem (1685.3 ± 309 ng/g), and PDOX tumors (1814 ± 110.3 ng/g) vs. 361.3 ± 1.5 ng/mL in serum. CT-179 alone was not active at 200 mg/kg in four models, although it was moderately effective at 240 mg/kg in one model. When combined with XRT, a significant extension of animal survival times was observed in two out of four models. Doses needed to eliminate OLIG2 expression in vitro varied from 0.3 to >1 µM in pGBM cells. In summary, our data showed that orally administered CT-179 penetrated the blood-brain barrier (BBB) and exhibited potential for inhibiting pGBM growth when combined with XRT.