RBIO-02. PERSONALIZED SCREENING OF RADIOSENSITIZATION BY A TGF-{beta} SMALL MOLECULE INHIBITOR USING CULTURED EXPLANTS OF HIGH GRADE GLIOMA (HGG) PATIENT SPECIMENS

High-grade gliomas (HGG) manifest profound radioresistance via cell-intrinsic and microenvironmental mechanisms. Transforming growth factor-β (TGF-β) is a key component of the HGG microenvironment, which we have shown enables radioresistance directly by enforcing an effective DNA damage response (DDR), and indirectly by promoting glioma stem cell self-renewal. Heterogeneity of HGG subtypes and patient differences raise the question of general utility of TGF-β inhibition for radiosensitization. Given the impact of microenvironment, we reasoned that personalized radiation biology could be attained by maintaining critical cell interactions. Here, we used HGG explant cultures as a patient-specific platform to test whether a prototypic small molecule inhibitor of the TGF-β type I receptor kinase, LY364947, compromises the DDR. Radiation induced -H2AX foci formation was used to assess the molecular recognition of DNA damage, and Sox2 and Notch1 intracellular domain (NICD) were evaluated as glioma stem cell self-renewal signals. Primary HGG (n=7) explants were established on raft inserts for 4 days, treated for 24 hr with LY364947 before irradiating with 2 Gy on day 5. Specimens were fixed 60 min later for immunofluorescence detection of markers. Collectively, radiation-induced -H2AX foci were reduced by 37% in LY364947-treated specimens compared to controls. Individual patient specimens ranged from showing no effect of LY364947 to a complete abrog...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: RADIOBIOLOGY Source Type: research