ESTRO 37 Abstract book

S1279

ESTRO 37

syndrome X-linked (ATRX) mutation and O 6 -methyl- guanine methyl transferase (MGMT) gene promoter methylation are associated with pseudoprogression disease (psPD) and pattern of recurrence in GBM patients after concurrent temozolomide (TMZ)-based chemoradia- tion. Material and Methods A total of 62 GBM patients were included in this retrospective study. Univariate logistic regression was used to evaluate the association between genetic factors and psPD or pattern of recurrence. Log rang test and Kaplan Meier were performed for the survival analysis. Results Of the 62 GBM patients, MGMT promoter methylation, IDH1 mutation and ATRX mutation were identified in 34 (54.84%), 8 (12.90%) and 10 (16.13%) patients, respectively. We found a significant association between MGMT promoter methylation and psPD (p<0.001), but not between IDH1 or ATRX mutations and psPD. MGMT methylated patients were more likely to show distant recurrence rather than treatment on field or marginal recurrence (p=0.032). GBM patients with psPD had a significant longer median overall survival and progression-free survival (21.8 and 16.14 months) than GBM patients with non-psPD (18.6 and 8.6 months). Conclusion Our results suggest that MGMT promoter methylation is associated with psPD and pattern of distant recurrence in GBM patients after TMZ-based chemoradiation. Additionally, psPD predicts a longer median survival and progression-free survival. EP-2319 Inhibition of anti-apoptotic Bcl-xL mitigates the radioresistance of mesothelioma cells M. Jackson 1 , M. Ashton 1 , A. Chalmers 1 1 Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom Purpose or Objective The incidence of mesothelioma continues to rise, whilst prognosis remains dismal due to a paucity of treatment options. Mesothelioma cells exhibit profound resistance to conventional therapies, including ionizing radiation (IR). Technological improvements in radiotherapy delivery have somewhat assuaged the difficulties associated with complex disease architecture, leading to a resurgence in interest in this modality. However, the intrinsic radioresistance of mesothelioma remains a barrier. Thus, development of a strategy to overcome resistance has the potential to improve greatly the applicability of radiotherapy, in this disease. This work aims to elucidate mechanisms of resistance of mesothelioma cells to IR and so identify and validate clinically-relevant targets for radiosensitization. Material and Methods The relative expression of proteins involved in the apoptotic pathway was assayed by Western immunoblotting following irradiation of mesothelioma cells. Viability and clonogenic assays were used to describe the radiosensitizing capacity of candidate small molecule inhibitors. Caspase-3/7 activity was measured to assess activation of apoptosis following combination treatment. Results The radioresistance of mesothelioma cells was confirmed in 2D and 3D culture systems. Following exposure to IR, mesothelioma cells were found to upregulate the anti- apoptotic Bcl-2 protein, Bcl-xL. Small molecule BH3- mimetic inhibitors of Bcl-xL, A1331852 and A1155463,

two receptors preferentially targeted by GLPG1790, closely matched the effects of the EPH pharmacological inhibition. GLPG1790 and radiation combined treatments reduced tumour mass by 83% in mouse TE671 xenografts. Conclusion Taken together, our data suggest that altered EPH signalling plays a key role in ERMS development and that its pharmacological inhibition might represent a potential therapeutic strategy to impair stemness and to rescue myogenic program in ERMS cells. EP-2317 The role of p21 in ionizing radiation induced premature senescence J. Wang 1 1 Institute of Modern Physics- Chinese Academy of Sciences, Biophysics, Lanzhou, China Purpose or Objective Cellular senescence can be triggered by diverse genotoxic stresses, such as telomere dysfunction, activated oncogenes, ionizing radiation and reactive oxygen species. Current investigations believe that the DNA damage response (DDR) signal, long term cell cycle arrest and activation of p53 or p16 pathway are responsible for stress-induced senescence. However, the molecular mechanisms of the long term arrested cells undergoing senescence are still unknown. Material and Methods Here we explored the molecular bases of cellular senescence by measuring senescence associated-β- galactosidase, protein expression levels and cell cycle progression in irradiated human melanoma A375 cells. Results Our results demonstrated that the DDR signal induced p21 accumulation in irradiateded cells. High levels of p21 expression led to senescent induction in A375 cells. p21 is a key factor to determine the fate of long-term G2 arrested cells. In p21-upregulated cells, high levels of p21 induced Aurora A kinase decline, which ultimately resulted in mitosis skip and senescence entry at tetraploid G1 phase. In contrast, cells without p21 expression could not induce Aurora A kinase degradation, which led to G2 arrested cells enter into M phase followed by apoptosis. Conclusion Together, we suggested that p21 upregulation coupled with Aurora A kinase decline is the key event in the process of senescence entry in G2 arrested cells. These deepening interpretation of cellular senescence following exposure of ionizing radiation will provide new insights into the radiotherapy. EP-2318 Molecular markers associated with pseudoprogression and recurrence pattern in glioblastoma. P. Nenclares Peña 1 , V. Rodríguez González 2 , D. Cantero Montenegro 1 , A. Hernández Laín 1 , J.F. Pérez-Regadera Gómez 2 1 Hospital Universitario 12 de Octubre, Pathology, Madrid, Spain 2 Hospital Universitario 12 de Octubre, Radiation Oncology, Madrid, Spain Purpose or Objective Molecular markers have become an integral part of tumour assessment in modern neuro-oncology and guide clinical decisions in gliomas. This study was conducted to analyse whether isocitrate dehydrogenase (IDH1) mutation, Alpha thalassemia/mental retardation