Abstract A44: The Pi3K inhibitor GSK2126458 is highly toxic in ovarian dysgerminoma

Abstract

Abstract Introduction: Mutations in PI3K/PTEN/Akt/mTOR have been implicated in the pathogenesis of numerous human carcinomas. Moreover, inhibitors of the phosphatidylinositol 3-kinase (PI3K) pathway are shown to be potent in several tumors, including ovarian adenocarcinomas. The effect of this class of agents on ovarian germ cell tumors, however, has not been previously studied. The aim of this work was to investigate cytotoxicity of the PI3K inhibitor GSK2126458 (a highly potent and selective compound) in ovarian dysgerminoma from a patient. Methods: The studied ovarian dysgerminoma was collected immediately following resection. Tumor sections (0.5×0.5×0.1 cm) were immersed in ice-cold RPMI medium gassed with 95% O2:5% CO2. The samples were then incubated at 37°C in RPMI (continuously gassed as above) with and without 50 nM GSK2126458 (Selleck Chemicals, cat. #S2658) for 150 min. At the end of the incubation period, specimens were processed for hematoxylin and eosin histologic stain. Results: Sections from untreated tissue revealed variable-sized tumor nests separated by fibrous stromal bands. Neoplastic cells were characterized by uniformly round central nuclei, clear-to-eosinophilic cytoplasm and prominent single nucleoli. Mitotic figures were abundant. Sections from treated tissue revealed a decrease in cellular density. Neoplastic cells demonstrated cytoplasmic disintegration, vacuolar degeneration and nuclear basophilia. Apoptotic bodies were numerous. Conclusions: GSK2126458 induced remarkable necrosis in the ovarian dysgerminoma. This preliminarily observation suggests sensitivity of this tumor to PI3K inhibition. The described in vitro methodology provides rapid assessment of the cytotoxicity of PI3K/PTEN/Akt/mTOR inhibitors.