EXTH-60. CONVECTION-ENHANCED DELIVERY OF EZH2 INHIBITOR FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA Free

Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brain tumor and the majority of patients with DIPG die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which prevents total surgical resection and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities. EZH2, histone methyltransferase of polycomb repressive complex 2, is a potential therapeutic target in DIPG. The study aims to assess the efficacy of EZH2 inhibitor by CED against DIPG xenograft model. The biodistribution of EZH2 inhibitor was evaluated by high-performance liquid chromatography (HPLC). HPLC analysis showed that the concentrationof EZH2 inhibitor in the brainstem tumor was only 3.74% of blood concentration by systemic administration. We treated mice bearing human DIPG xenografts with EZH2-inhibitor using intraperitoneal or CED administration. Intracranial tumor growth was monitored by bioluminescence image and therapeutic response was evaluated by animal survival. CED of EZH2 inhibitor suppressed tumor growth and significantly extended animal survival in compared to intraperitoneal administration of EZH2 inhibitor (P=0.0475). Taken together, our results indicate that CED of EZH2 inhibitor would provide an alternative strategy for bypassing the BBB and increasing efficacy of EZH2 inhibitor for the treatment of DIPG.