EPCT-19. DRUG RESISTANCE IN MEDULLOBLASTOMA ADDRESSED WITH OLIG2 INHIBITOR, CT-179

Patients with medulloblastoma, the most common malignant pediatric brain tumor. need improved treatment options. Conventional medulloblastoma treatment, with resection, chemotherapy, and radiation, leaves survivors at risk of neurocognitive injury, growth defects, and psychosocial impairment. Moreover, there is no effective therapy for recurrent medulloblastoma. We seek to identify novel treatments that will address systemic toxicity and tumor recurrence. We tested a nanoparticle formulation of the CDK4/6 inhibitor, palbociclib (POx-palbo) in mice genetically-engineered to develop medulloblastoma (G-Smo mice) and found a significant anti-tumor effect that was consistently limited by the recurrence of OLIG2+ medulloblastoma stem cells. We then tested the hypothesis that directly targeting OLIG2 function would improve the efficacy of palbociclib and forestall resistance. We therefore examined the potential efficacy of CT-179, a first-in-class OLIG2 inhibitor, in G-Smo mice engineered to express luciferase as an SHH reporter. These studies showed that CT-179 decreased SHH signaling and prolonged event-free survival. Pharmacodynamic studies of G-Smo mice during treatment showed that CT-179 alters cell-cycle progression and promotes a shift towards cell-cycle arrest. Mechanistically, CT-179 decreased the Olig2 phosphorylation. The combination of CT-179 and POx-palbo increased event-free survival of G-Smo mice compared to either agent administered alone. Our studies show both the potential of the palbociclib CT-179 combination, and the potential for CT-179 to improve the efficacy of therapies limited by OLIG2+ stem cell recurrence. As OLIG2+ stem cells have been shown to drive recurrence to conventional therapy and OLIG2 phosphorylation disables p53-driven apoptosis, CT-179 may be a versatile agent to enhance both targeted and cytotoxic treatments.