ESTRO 36 Abstract Book

S110 ESTRO 36 _______________________________________________________________________________________________

radiotherapy and chemotherapeutic agents which act as radiosensitisers. In assessing the efficacy of drugs as radiosensitising agents, it is important to determine their effects on normal tissues as well as tumours. We have developed a modified crypt assay to assess acute toxicity on bowel surrounding the bladder in vivo. Furthermore, as murine small intestine is exquisitely sensitive to the doses of radiation used, we have developed an irradiation method which avoids the small intestine, using a small animal radiation research platform (SARRP), to assess late bowel toxicity associated with bladder cancer radiotherapy. Our methods should help identify those agents which may be suitable to take forward to clinical trials. SP-0219 Optimising the output of preclinical lung models to optimize the chances of succes into the clinic. E. Deutsch 1 1 Institut Gustave Roussy, Villejuif, France Despite the numerous promising preclinical data, increasing the therapeutic efficacy of chest radiotherapy using novel drugs-radiotherapy combinations has often failed to show promise in the frame of clinical trials.In some cases, these novel approaches failed to increase the anti-tumor efficacy of standard radiotherapy suggesting that preclinical models were not appropriate enough to recapitulate the complexity and the most recent advances in our understanding of tumor biology (i.e. the spectrum of mutational events, the tumor/immune host interactions..). In other cases, new drugs- radiotherapy combinations induced severe toxicities that justified the discontinuation of clinical development plans. This underscores the fact that in many circumstances, preclinical models have been overlooking normal tissue response to radiotherapy. As an illustration of this, major monoclonal antibodies used in the clinic such as anti EGFr or anti VEGF were developed in the clinic on the basis of preclinical rationale that were not able to detect any impact on normal tissue response. Another reason for these limited effects is the fact that many preclinical experiments fail to associate and to combine with chemoradiation and use radiation alone as a comparator. The development of orthotopic, syngenic tumor models offers the opportunity to evaluate within the same series of experiments both the normal tissue and the tumor response. The rising interest in the field of immuno oncology is also increasing our need for such models since the immune / stromal component which is not only an emerging player during tumor response to radiotherapy. As an illustration of this, we will present data from our group underscoring the fact that modulating the immune stroma affects normal response of the normal lung to radiotherapy. We make the make the assumption that such models could be a mean to minimize the early discontinuation of new drugs radiotherapy clinical trials and eventually to increase the patients’ clinical benefit as the results of a better selection of novel therapeutic that would not impair, and if possible enhance, the tumor versus normal tissue clinical ratio. OC-0220 Exploiting novel combined-modality approaches for treatment of highly aggressive pancreas carcinomas M. Orth 1 , L. Posselt 2 , S. Kirchleitner 2 , J. Schuster 1 , C. Belka 1 , M. Schnurr 2 , K. Lauber 1 1 LMU Munich, Department of Radiation Oncology, Munich, Germany 2 LMU Munich, Department of Clinical Pharmacology, Munich, Germany Purpose or Objective Pancreatic ductal adenocarcinoma (PDAC) is a cancer entity with growing prevalence and very poor prognosis.

The survival rates are limited to approximately 25% of patients after one year and only 5% after five years, respectively. Standard treatment encompasses surgical resection (if possible) accompanied by radiotherapy, chemotherapy and/or palliative care. However, treatment failure is frequent, and inherent resistance towards radio- and/or chemotherapy is considered as one major reason. Accordingly, novel treatment approaches are needed, which can address this resistance and which are able to create synergisms with the classic therapy modalities. Material and Methods A panel of human PDAC cell lines was subjected to clonogenic survival assays, and scores of radioresistance were extracted by principal component analysis. Next, the relative expression levels of DNA damage response (DDR) genes were analyzed by qRT-PCR, and correlation analyses were employed in order to identify potential drivers of radioresistance. Specific inhibitors targeting the respective candidates were examined in terms of their potential to sensitize PDAC cell lines towards radiotherapy. The obtained results were confirmed by RNA interference. The clinical relevance of the identified target genes was evaluated in the TCGA PDAC data set. Finally, an orthotopic PDAC model with fractionated CT- based irradiation was established in order to evaluate the therapeutic potential of our approach in vivo. Results Using a cohort of nine human PDAC cell lines, we identified several crucial components of the DNA damage response (DDR) machinery to be upregulated in the radioresistant cell lines, including ATM and DNA-PKcs. The impact of both kinases on clonogenicity was examined both by pharmacological inhibition and RNA interference. We found that inhibition and siRNA-mediated knockdown of DNA-PKcs significantly diminished the clonogenic potential of radioresistant PDAC cell lines. Using the TCGA PDAC collective, we found that expression of DNA-PKcs is elevated in about 11% of all samples and that this upregulation is associated with a striking decrease in overall survival. Currently, the in vivo efficacy of DNA- PKcs inhibition in combination with fractionated radiotherapy is tested in an orthotopic mouse PDAC model. Conclusion The poor prognosis of pancreatic ductal adenocarcinoma urgently demands for the development of novel treatment approaches. We show that pharmacological inhibition of the DDR-related kinase DNA-PKcs gives rise to a novel, highly promising treatment approach which should be further explored in the future. OC-0221 High-performance radiosensitivity assay to predict post radiation overreactions G. Vogin 1 , L. Bodgi 2 , A. Canet 2 , S. Pereira 2 , J. Gillet- Daubin 2 , N. Foray 3 1 Institut de Cancérologie de Lorraine & UMR 7365 CNRS- UL, Academic Department of Radiation Oncology, VANDOEUVRE-LES-NANCY Cedex, France 2 Neolys Diagnostics, R&D, Lyon, France 3 Cancer Center of Lyon- UMR Inserm 1052 CNRS 5286 CLB, Radiobiology, Lyon, France Purpose or Objective Between 5 and 15% of patients treated with r adiation experience toxicity considered "unusual" that can lead to serious sequelae. Identifying those patients prior treatment would therefore have sound positive clinical implications. Retrospective analysis on skin biopsies from patients treated by radiotherapy to define a radiobiological parameter with the highest predictive performance that can be used as a reliable predictor of

post-treatment toxicity. Material and Methods

Immunofluorescence experiments were performed on the COPERNIC collection of 116 skin fibroblasts irradiated at 2