Abstract 2488: Stat3 inhibitor (BBI-608) with radiation therapy is promising in malignant pleural mesothelioma

Abstract

Abstract Background: The prognosis of Malignant pleural mesothelioma (MPM) is very poor, the new drug for MPM is need. IL-6 in serum with MPM patients is high, IL-6/Stat3 pathway is activated. We investigated that Stat3 is the potential target for the treatment of MPM. Methods: Cell viability was assayed with Cell Counting Kit-8 (CCK-8: WST-8 Dojindo). MPM cells (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, MSTO-211H) were seeded into 96-wellplates. After the treatment with Stat3 inhibitor (BBI-608). Cell Counting Kit-8 solution was added to each well of the plate and measured the absorbance using a microplate reader. The levels of phosphorylated Stat3 (p-Stat3) were measured in cell lysates using an InstantOne ELISA assays (eBioscience). The translocated p-Stat3, c-Myc were analyzed by Confocal immunofluorescent. In vivo study, H226 cells were injected into the subcutaneous over the flank region of nude mice. Mice were randomly assigned into four groups (5 mice each group) 1) vehicle control 2) treated with BBI-608 3) Radiation 4) BBI608/RT. Tumor is measured twice per week. Results: BBI-608 inhibited MPM cell lines (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, MSTO-211H) viability in a dose-dependent manner. The level of p-Stat3 was decreased 90% by BBI-608 10μM treatment in H226. Untreated H226, p-stat3 was observed in cytoplasma and localized in the nucleus. As compared with untreated cells, p-stat3, c-Myc were decrease in cytoplasma and was not localized in the nucleus with BBI-608 treated cells. BBI-608 suppressed tumor growth (p<0.05) and completely suppressed tumor growth with radiation in mouse model. Conclusion: In this study, we have shown that BBI-608 inhibited the proliferation of all MPM cell (epithelial, biphasic, sarcomatoid) lines and inhibited Stat3 phosphorylation and blocked the translocation to the nucleus. We also demonstrated that BBBI-608 completely suppressed tumor growth with radiation in mouse model. Furthermore, Stat3 inhibitor with Radiation Therapy (START) is promising in MPM therapy. Citation Format: Seiji Matsumoto, Hiroshi Doi, Tohoru Nakamichi, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa. Stat3 inhibitor (BBI-608) with radiation therapy is promising in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2488.