Abstract B46: Inhibition of STAT3 enhances the radiosensitizing effect of Temozolomide in vitro and in vivo: Validation using patient-derived glioblastoma model

Abstract

Abstract Background and purpose: Despite aggressive treatment with radiation therapy plus temozolomide (TMZ), the prognosis for glioblastoma remains poor. We investigated the potential of targeting signal transducer and activator of transcription-3 (STAT3) to improve the therapeutic outcome of glioblastoma. Material and methods: We evaluated the preclinical potential of a STAT3 inhibitor, Cpd188 combined with temozolomide and radiation in vitro assays using two established glioblastoma cell lines (U251, U87) and two patients-derived glioblastoma cell lines (GBL12, GBL28) and in vivo studies using nude mice bearing intracranial U251 xenografts. Results: Cpd188 potentiated the radiosensitizing effect of TMZ in U251 cell which has high levels of p-STAT3 expression. Increased radiosensitizing effects of TMZ were associated with impaired DNA damage repair, apoptosis and the reversion of epithelial-mesenchymal transition (EMT). Cpd188 delayed in vivo tumor growth both alone and in combination with radiation and TMZ. We also confirmed the radiosensitizing effect of Cpd188 of GBL28 cell which was originated from a patient with high level of STAT3 expression and unmethylated MGMT. Conclusion: Targeting STAT3 using Cpd188 could be a viable therapeutic approach to improve the outcome of current standard therapy for glioblastoma patients having high p-STAT3 expression regardless of MGMT methylation status. *Work supported by the grant (#2013R1A1A2074531) from the Ministry of Science, ICT & Future Planning to In Ah Kim Citation Format: Tae Jin Han, Eun Jung Choi, Bong Jun Cho, Sang Hyuk Song, Sun Ha Paek, In Ah Kim{Authors}. Inhibition of STAT3 enhances the radiosensitizing effect of Temozolomide in vitro and in vivo: Validation using patient-derived glioblastoma model. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B46.