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Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor. Radiation, the standard of care, extends life for 6-18 months but has never cured a patient. Therefore, the discovery of novel treatments is imperative. DIPG tumors have elevated baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that allows cells to tolerate various forms of stress. Increased expression of activating transcription factor 4 (ATF4) indicates activation of the ISR. Low levels of ATF4 protect cells from stress, while sustained high-levels of ATF4 result in cell death. Because DIPG has a high baseline level of ATF4, we hypothesized that the ISR activators Sal003 and ONC201 would synergize and kill DIPG cells. After determining the IC25 of Sal003 and ONC201, we treated three patient-derived cell lines: JHH-DIPG1, SF-7761, and JHH-DIPG16A with low micromolar doses. To measure proliferation, we performed immunofluorescence staining for bromodeoxyuridine (BrdU) incorporation. The combination treatment significantly reduced BrdU incorporation (JHH-DIPG1 p=0.0026, SF-7761 p=0.0002, JHH-DIPG16A p Citation Format: Orlandi V. Novak, Antje Arnold, Charles Eberhart, Eric H. Raabe. Combination therapy activating the integrated stress response synergistically suppresses proliferation and induces apoptosis in diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5227. |
