ESTRO 36 Abstract Book

S540 ESTRO 36 2017 _______________________________________________________________________________________________

induce loco-regional recurrence (significant for tumors collected 4 days after 5x2Gy). Furthermore, based on the metabolic profile of the primary MDA-MB231 tumors and OPLS linear regression, mathematical models were established in the different groups allowing to predict the metastatic burden (r²=0,80-0,90). Conclusion In preclinical models, we show profound modifications of the primary tumor metabolome following NeoRT through NMR analyses, offering new opportunities to understand tumor metabolism adaptation following NeoRT. Furthermore, others NMR results appear very relevant when transposed to clinic. Indeed, with mathematical models, local recurrence and metastatic profiles were predictable based on the metabolomic profile of the primary tumor at the time of surgery, which could be helpful to adapt adjuvant therapies in order to prevent relapse. PO-0986 Downregulation of the oncoprotein SET enhances RT-induced apoptosis in hepatocellular carcinoma C.Y. Huang 1 , M.H. Hung 2 , C.W. Kuo 3 , C.T. Shih 4 , M.H. Chen 4 , K.F. Chen 5 1 National Taiwan university hospital, Division of Radiation Oncology- Department of Oncology, Taipei, Taiwan 2 Taipei Veterans General Hospital, Division of Medical Oncology- Department of Oncology, Taipei, Taiwan 3 Yuanpei University of Medical Technology, Department of Medical Imaging and Radiological Technology, Hsinchu, Taiwan 4 National Yang-Ming University, Institute of Biopharmaceutical Sciences, Taipei, Taiwan 5 National Taiwan university hospital, Department of Medical Research, Taipei, Taiwan Purpose or Objective Hepatocellular carcinoma (HCC) is among the most lethal human malignancies worldwide. Radiotherapy (RT) is not commonly used to treat HCC with regard to both suboptimal treatment efficacy and toxicity. The current project aimed to characterize the role of a novel oncoprotein SET/ I2PP2A (Inhibitor-2 of protein phosphatase 2A) in mediating the radio-resistance of HCC cell and explore the potential on antagonizing SET to improve the anti-HCC effects of RT. Material and Methods The effects of RT in HCC cells with different expression of SET were assessed by colony formation and sphere formation assay. We generated a novel SET antagonist, EMQA (N 4 -(3-ethynylphenyl)-6,7-dimethoxy-N 2 -(4- phenoxyphenyl) quinazoline-2,4-diamine), to validate the therapeutic potential of targeting SET. The combination effects of EMQA and RT were tested in vitro using four different HCC cell lines, Hep3B, PLC5, HA22T and HA59T, and a subcutaneous PLC5 xenografted model in vivo. HCC cells were exposed to 1 fraction of 4-Gy radiation using a cobalt 60 unit (at a dose rate of 0.5 Gy/min) with the source-axis-distance set at 80 cm to the bottom of the dish. After 48 hours, the cells were treated with or without EMQA. Results To explore the roles of SET in affecting the radio- sensitivity in HCC, we first generated PLC5 and Hep3B cells with different SET activity, and assessed the effects of RT on these cells by colony formation and tumor sphere assay. Comparing to mock-treated cells, HCC cells transfected with shRNA against SET were shown with significant reduced viability under the same RT treatment. Oppositely, cells with ectopic expression of SET were more resistant to RT. Next, we used EMQA to test whether antagonizing SET could enhance the effects of RT against HCC. Using sub-G1 analysis, we showed that adding EMQA significantly increased RT-induced apoptosis of HCC cells.

The number of tumor colony was also significantly decreased in HCC cells exposing to EMQA plus RT than either of the treatment alone. Lastly, using the PLC5 xenografted tumor model, the synergistic effects of SET antagonist combining RT were also observed. Conclusion SET is a novel oncoprotein that affects the radio - sensitivity of HCC cells. A combination therapy with RT and the SET antagonist, such as EMQA, enhanced RT- induced apoptosis of HCC cells in vitro and in vivo. PO-0987 Gemcitabine-based chemoradiotherapy gets improved with PARP inhibitor in pancreatic cancer cells W. Waissi 1 , H. Burckel 1 , E. Magisson 1 , G. Larderet 1 , G. Noel 1 1 CLCC Paul STRAUSS, EA3430- Laboratoire de Radiobiologie, Strasbourg, France Purpose or Objective Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a cumulative 5-year overall survival of less than 5% for all stages. Thirty percent of patients diagnosed with pancreatic adenocarcinoma present with a locally advanced disease and could benefit from chemoradiotherapy with gemcitabine, which is effective but toxic. Over the past few years, studies have focused on the development of targeted radiosensitizer such as poly(ADP-ribose) polymerase (PARP) inhibitor. We conducted this in vitro study to determine whether PARP inhibition enhances radiation-induced cytotoxicity of pancreatic adenocarcinoma. Material and Methods Pancreatic carcinoma cells, MIA PaCa-2 (BRCA1/2 wild- type) , were treated with olaparib and/or gemcitabine and/or irradiation (2,5 and 10 Gy). In vitro cell viability, clonogenic assay, cell cycle distribution, γ-H2AX quantification, apoptosis and autophagy were assessed. Results In vitro, treatment with olaparib alone at 1 µM was not cytotoxic but highly radiosensitized cells (standard enhancement ratio =1.23+/-0.02) and particularly at high dose per fraction (10 Gy). After 24 hours, the number of remaining γ-H2AX stained cells was higher when cells were treated with a combination of 10 Gy irradiation and olaparib compared to irradiation or olaparib alone. Furthermore, combination of olaparib and irradiation induced a G2/M arrest. In contrast, a non-cytotoxic concentration of gemcitabine could also radiosensitize cells, but clearly less than olaparib (SER=1.11+/-0.04). Radiosenzitization by gemcitabine was associated with percentage of cells blocked in early S-phase just before irradiation. Finally, cell death quantification after 24 hours showed that none of the treatments induced apoptosis, whereas gemcitabine or 10 Gy irradiation alone induced autophagy. Conclusion Our results showed that MIA PaCa-2 cells could be radio sensitized with low dose of olaparib , through an increase of unrepaired double-strand breaks and a block in G2 phase. The radiosensitization was higher with high dose radiation. This may be translated into an enhancement of local control in vivo and better disease free survival. Investigations in three other pancreatic cells lines are in progress. PO-0988 Following tumour microenvironment after Neoadjuvant radiotherapy with IVIM perfusion analysis F. Lallemand 1 , N. Leroi 2 , M. Bahri 3 , E. Balteau 3 , A. Noël 2 , P. Coucke 1 , A. Plenevaux 3 , P. Martinive 1 1 C.H.U. - Sart Tilman, Radiothérapie, Liège, Belgium 2 ULg, Laboratory of Tumor and Development Biology, Liège, Belgium 3 ULg, Cyclotron Research Center, Liège, Belgium

Purpose or Objective