DDRE-15. THE COMBINATION THERAPY OF PARP INHIBITOR AND TMZ IN DIFFUSE MIDLINE GLIOMA HARBORING H3 K27M-MUTANT

Abstract

Abstract Diffuse midline glioma harboring H3 K27M-mutant (DMG) is a newly defined entity, and the prognosis of DMG is very poor. Combined of radiotherapy and chemotherapy is a standard therapeutic approach, because surgical debulking for providing relief to patients is not an option. Temozolomide (TMZ) is often used for the treatment of gliomas. TMZ is an alkylating agent that adds a methyl group to DNA (O6-guanine, N7-guanine, and N3-adenine). TMZ-induced cytotoxicity is mainly derived from O6-methylguanine, which is repaired by O6-methylguanine DNA methyltransferase (MGMT). Unfortunately, most DMG lacks MGMT promoter hypermethylation, which contributes to less effectiveness of TMZ in DMG. Because N7-methylguanine and N3-methyladenine are repaired via base excision repair, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor combined with TMZ was considered to be effective to suppress the proliferation of DMG. The purpose of the study is to evaluate whether PARP inhibitor sensitizes DMG to TMZ. A patient-derived DMG cell line, SF8628, showed the expression of MGMT, resulted in resistant to TMZ. We evaluated the effects of multiple PARP inhibitors: talazoparib, olaparib, niraparib, A-966492 in SF8628 DMG cells. These PARP inhibitors suppressed the proliferation of SF8628 cells in a dose dependent manner. Moreover, PARP inhibitors enhanced TMZ-induced cytotoxicity in SF8628. The combined treatment of PARP inhibitor and TMZ induced apoptosis. These results would support a possibility that the combination treatment of PARP inhibitor and TMZ is an effective approach in DMG.