RBIO-11. BASAL BCL-2-INTERACTING MEDIATOR OF CELL DEATH (BIM) RESPONSIVENESS CORRELATES WITH RADIOSENSITIVITY IN MENINGIOMA

Abstract

Abstract INTRODUCTION Radiotherapy remains the primary adjunctive treatment for recurrent or progressive meningioma. Nevertheless, varied clinical response to radiotherapy in meningioma remains a challenge, particularly in higher grade tumors. Currently there is a paucity of predictors of radio-sensitivity. Bim peptide is an intrinsic mediator of apoptosis, and Bim-responsiveness has been postulated as a metric of general sensitivity to apoptotic stress. Herein we investigated its utility as a metric of radio-sensitivity in meningioma. METHODS In an in vitro model of meningioma, a number of immortalized human and murine meningioma cell lines and patient-derived primary cultures (WHO grades 1 + 2), were exposed to ionizing radiation at range of doses (0, 2, 4, 8, 16Gy); cells were counted (Celigo, Nexelcom) to assess for growth. Separately, cultures were irradiated at 4Gy and apoptosis was analyzed 24H later using Annexin/PI staining by flow cytometry (Attune NxT). Lastly, untreated cultures were exposed to Bim peptide as a range of doses (0.01uM-10uM); induction of apoptosis was assessed via cytochrome C staining by flow cytometry. RESULTS We were able to recapitulate a wide range of radio-sensitivities both by growth metrics and radiation-induced apoptosis. Immortalized lines showed more radiation-induced growth inhibition relative to primary cultures (p = 0.03). Activation of apoptosis in response to Bim exposure demonstrated a similarly wide range of basal apoptotic sensitivities, akin to that seen for radio-sensitivity. In fact, there was a significant correlation (Pearson, p < 0.01) between Bim-responsiveness and levels of radiation-induced apoptosis. CONCLUSIONS We identify basal state Bim-responsiveness as a potential predictor of radio-sensitivity in meningioma. Further work in this vein may shed light on mechanisms of radio-resistance in meningioma, particularly with respect to the interaction of Bim with the anti-apoptotic members of the Bcl-2 family.