Abstract 2827: Application of AZD2281 combine with radiation therapy in glioblastoma

Abstract

Abstract Glioblastoma (GBM), can be divided into primary tumors from brain tissue (>90% of all cases) and secondary tumors that progress from low-grade gliomas. The current GBM treatment strategy is chemotherapy drug temozolomide (TMZ) combined with radiotherapy (RT), which has limited treatment effect, poor prognosis, high recurrence rate, and short prognosis survival time. Recently, studies indicated that breast cancer susceptibility gene 1/2 (BRCA1/2) mutations are frequently occur in GBM, while few studies have explored this pathway in depth. At present, AZD2281 (PARP Inhibitor) has been used to treat breast cancer and ovarian cancer patients with BRCA1/2 mutation...etc. Whether AZD2281 can play a role in affecting the relevant pathways after BRCA1/2 mutate GBM patients, and the possible mechanism and benefit of combined RT are the focus of this study. AZD2281 is the first Poly (ADP-ribose) polymerase (PARP) inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of germline BRCA mutation-associated ovarian cancer. AZD2281 is a targeted therapy that used to block DNA Damage Response (DDR) in cells/tumors deficient in homologous recombination repair (HRR). After RT, there may be a phenomenon of DNA repair; therefore, AZD2281 can be used to disrupt the repair process. At the beginning, we used RSI analysis to confirm that patient with higher expression level of BRCA1 may relatively resistance to RT. To overcome this issue, we identified the effect of AZD2281 combined with RT on GBM cells (BRCA1/2 higher and lower expression cells) by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT assay), and colony formation. The internal/external apoptosis pathways (Caspase-3/Caspase-8/Caspase-9) and TUNEL assay were used to prove the superior apoptosis effect of AZD2281 combined with RT as compared to single treatment. Additionally, cells lower BRCA1 expression level (U87 and U251 siBRCA1) may sensitive to RT treatment. In our DNA damage, DNA fragmentation, and transwell invasion/migration results, we showed that the combination of AZD2281 and RT may effective induce DNA damage. In our animal data, we proved that combination therapy can effective suppression tumor growth and apoptosis-related protein signaling increased in DNA damage by IHC (p-ATM/p-CHK2/Caspase-3/Caspase-8/Caspase-9). In conclude, we suggested that AZD2281 can be used as a radiosensitizer to sensitize GBM patient to RT, which is dependent to BRCA1 expression. Citation Format: Tsal-Lan Liao, I-Tsang Chiang, Yuan Chang, Fei-Ting Hsu. Application of AZD2281 combine with radiation therapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2827.