Abstract 6901: Imipridones (ONC201, ONC206 and ONC212) modulate MGMT and ClpX expression in DIPG cell lines

Abstract The first-in-class small-molecule imipridone ONC201/Dordaviprone targets mitochondrial protease ClpP to disrupt oxidative phosphorylation and trigger integrated stress response (ISR), TRAIL/DR5, and tumor cell death. ONC201 and analog ONC206 and ONC212 are blood-brain barrier penetrant. Temozolomide (TMZ) is an oral alkylating agent that is generally well tolerated. Epigenetic transcriptional silencing of O6-methylguanine-DNA methyltransferase (MGMT) mediated by MGMT gene promoter methylation is associated with response to TMZ treatment. TMZ has been used in combination with Radiation Therapy (RT) as standard of care for glioblastoma (GBM) with a methylated MGMT promoter since 2005. Our previous studies demonstrated that ONC201/ONC206 synergized with standard-of-care GBM therapies TMZ and RT in GBM cell lines and orthotopic GBM mouse model. Diffuse Intrinsic Pontine Gliomas (DIPG) is a fast growing and highly aggressive pediatric central neural system tumor that starts in the brain stem's glial cells and has a dismal prognosis. DIPG has been recognized to be molecularly distinct from both adult high-grade glioma (HGG) and other non-midline pediatric high-grade gliomas (pHGG). DIPG has almost universally unmethylated MGMT promoters and TMZ has no role in the treatment of this disease. We reported earlier that ONC201 suppresses oxygen consumption rate observed with TMZ alone in DIPG cells, and TMZ has effects on T-cells killing solid tumor cells with high expression of MGMT. In this study we discover that imipridones (ONC201, ONC206 and ONC212) reduce expression of MGMT in DIPG cell lines following treatment with Imipridones -/+ TMZ. ClpX levels were reduced in all glioma cells treated and served as a biomarker of imipridone target engagement. The change of MGMT has the same trend as that of ClpX. These novel findings suggest a potential mechanism of synergy between imipridones and TMZ through suppression of MGMT protein expression in DIPG cells that typically have unmethylated MGMT promoter and are resistant to effects of TMZ. We are going to test this mechanism of synergy and therapeutic efficacy in vivo by treating orthotopic DIPG mouse models with imipridones -/+ TMZ. Our results support further studies combining imipridones (ONC201, ONC206 and ONC212) with TMZ and RT as a reasonable and safe therapeutic option for DIPG. Citation Format: Lanlan Zhou, Shengliang Zhang, Wafik S. El-Deiry. Imipridones (ONC201, ONC206 and ONC212) modulate MGMT and ClpX expression in DIPG cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6901.