P11.63 PI3K inhibition in conjunction with the ketogenic diet reduces growth and neuroinflammation in pediatric high-grade glioma

Abstract

Abstract Background: Pediatric high-grade glioma remains a poorly treatable disease with high mortality.Therapeutic advances have lagged behind that of adult glioblastoma, due to small patient numbers, inappropriate generalization from adult tumor types, and unique biology. The use of targeted therapy has recently gained interest in this disease, but efficacy is limited by therapeutic resistance, often as a result of tumor heterogeneity. In the case of phosphatidylinositol 3-kinase (PI3K) inhibition, clinically relevant PI3K inhibitors represent a strong class of drugs for pediatric high-grade glioma, but their use is associated with insulin feedback that reactivates the PI3K pathway and drives therapeutic resistance. Here, we target insulin feedback that is the primary mechanism of PI3K inhibitor-related therapeutic resistance in pediatric high-grade glioma using the ketogenic diet. Materials and Methods: Patient-derived pediatric high-grade glioma stem cells were treated with vehicle or the pan-PI3K inhibitor, BKM-120, with glucose deprivation or phenformin to decrease glucose utilization. NSG mice containing patient-derived pediatric high-grade glioma xenografts were treated with vehicle or BKM-120 on a regular or ketogenic diet to determine whether reducing insulin feedback increases BKM-120 efficacy. To determine the effect of glioma cells on neuro-inflammation, we measured pro-inflammatory cytokines in glioma cells treated with BKM-120 and phenformin in comparison to vehicle-treated cells. We then applied conditioned medium from glioma cells treated with BKM-120 and phenformin to cortical neuronal cultures to measure oxidative stress and neuro-inflammation. Results: Pediatric high-grade glioma cells exhibited increased toxicity when exposed to BKM-120 with glucose deprivation or phenformin. Furthermore, mice with intracranial high-grade glioma xenografts survived longer when treated with BKM-120 on the ketogenic diet than with BKM-120 or the ketogenic diet alone. Phenformin reduced the production of pro-inflammatory cytokines by BKM-120-treated glioma cells. Cortical neurons treated with conditioned medium from BKM-120- and phenformin-treated glioma cells exhibited less oxidative stress than those treated with BKM-120 alone. Our results demonstrate that strategies to lower glucose utilization and insulin feedback increase efficacy of BKM-120 and decrease neuro-inflammation. Conclusions: We show that strategies to lower glucose utilization and insulin feedback increase efficacy of BKM-120. Furthermore, reducing insulin feedback decreases the production of pro-inflammatory cytokines in tumor cells and reduces oxidative stress in neurons treated with conditioned medium from BKM-120-treated glioma cells. By using the ketogenic diet to reduce glucose levels, this strategy may enhance efficacy of PI3K inhibitors in this patient population.