Abstract Book

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ESTRO 37

maintenance machinery in tumorigenesis, including chromosomal instability and molecular basis of APOBEC- linked tumor mutational signatures; 4. DNA damage response, including checkpoint and repair pathways, as emerging treatment targets and biomarkers in oncology. Apart from molecular mechanistic insights, translational aspects and clinical relevance for cancer treatment will be discussed whenever applicable, also in relation to ionizing radiation. P. Hamerlik 1 , R. Rikke Darling Rasmussen 1 , E. Elisabeth A. Obara 1 , K. Kamilla E. Jensen 1 , D. Diana A. Morante 1 , A. Alex F. Hernandez 1 , C. Christoffel Dinant 1 , J. Jiri Bartek 1 1 Danish Cancer Society Research Center, Danish Cancer Society Research Center Brain Tumor Biology, Copenhagen, Denmark Abstract text Rampant genomic instability is a hallmark of glioblastoma (GBM). Despite recent advances in our understanding of this deadly disease, molecular mechanism contributing to treatment resistance are poorly understood. In spite of concerted efforts, molecular mechanisms/genes causing high recurrence and treatment resistance are poorly understood. The tumor suppressor BRCA1 plays a critical role in maintaining genomic stability, in general, and replication stress (RS), in particular. Numerous reports have demonstrated that wild type BRCA1 loss impairs the growth of several cancers (breast, ovarian, lung, prostate and colon). Our data show considerably higher level of RS in malignant gliomas compared to other solid tumors (breast, prostate ovarian) and identified a novel role for BRCA1, where high BRCA1 expression negatively associates with glioma patient survival and plays an unexpected tumor-promoting role in GBM. Histone chaperones regulate chromatin structure and gene expression through interaction with histones and RNA polymerase II. Spt6 is a highly conserved transcription elongation factor and histone chaperone. We have identified a novel role of Spt6 in glioblastoma-derived cancer stem-like cells (GSCs) using high-throughput siRNA microscopy-based screening. Our data show that the loss of Spt6 in GSCs, but not their differentiated counterparts (non-GSCs), results in decreased proliferation rates, cell cycle arrest and increased double-strand DNA breaks due to hyper-activation of error-prone non-homologous end- joining DNA repair (NHEJ). Importantly, shRNA-mediated knockdown significantly impairs tumor initiation capacity of GSCs and extends survival of tumor-bearing mice. Our findings indicate an important role of Spt6 in glioblastoma maintenance and resistance to DNA damaging therapies. SP-0451 The translational impact of targeting DNA repair A. Chalmers 1 1 Inst. of Cancer Sciences-Univ. Glasgow, Department of Clinical Oncology, Glasgow, United Kingdom Abstract text The use of PARP inhibitors as single agents in the treatment of BRCA deficient breast and ovarian cancer is now well established, and their use in a broader range of homologous recombination defective tumours is currently being explored. Clinical application of PARP inhibitors in combination with radiation has also been under investigation for several years now and, while knowledge about effects on normal tissue toxicity is accruing, evidence of improved tumour control is still awaited. In the meantime, small molecule inhibitors of a range of DNA damage response proteins have been developed and SP-0450 Replication stress as a driver of genomic instability in malignant gliomas

pre-clinical data indicates that some of these may be more potent radiosensitizers than PARP inhibitors. In this presentation I will summarize the key pre-clinical findings in this area and review the early phase clinical trial data for radiation-DDRi combinations, with reference to the challenges encountered when cytotoxic chemotherapy drugs are also added. Subsequently I will consider how we might select patients for particular radiation-DDRi combinations, and present clinical trial designs with potential to accelerate progress in this promising field of research.

Symposium: The evolving role of radiotherapy in the management of lung cancer

SP-0452 Towards individualised dose-constraints for dose-limiting toxicity R. Bütof 1 1 University Hospital and Medical Faculty Carl Gustav Carus- Technische Universität Dresden- Germany, Department of Radiation Oncology, Dresden, Germany Abstract text In radiation therapy of non-small cell lung cancer (NSCLC), the major problem is the high rate of local recurrences. To overcome this, estimated tumor control doses > 80 Gy are needed, which can only be reached using individualised maximum tolerable doses. Some recent ( in silico planning) studies have shown that individualised dose prescription based on normal tissue constraints enables dose escalation without increasing toxicity rates in patients with NSCLC [1-4]. Modified fractionation schemes could also add to decreasing dose- limiting toxicity in lung cancer irradiation [2]. Another important aspect towards individualisation is the development of biological and/or biomarker-driven normal tissue dose-constraints for specific patients. One possible example, well-known from preclinical data, is the heterogeneous radiosensitivity of different parts of the lung and heart. This may be one starting point for the development of individualized dose-constraints in the clinic. Furthermore, determination of pre-existing damages of organs by specific imaging techniques would allow for an individualisation and therefore reduction of toxicity rates [5]. Finally, the prediction of organ toxicity, e.g. , heart failure or pneumonitis, using genetic analyses has been demonstrated in some studies [6]. Overall, one major aim should be the development of predictive scores for individual toxicity composed of functional imaging data and functional clinical parameters in order to adapt dose-constraints in each individual patient. [1] van Baardwijk et al. 2008; Radiation dose prescription for non-small-cell lung cancer according to normal tissue dose constraints: an in silico clinical trial. Int J Radiat Oncol Biol Phys. 71(4):1103-10. [2] van Baardwijk et al. 2008; Individualized radical radiotherapy of non-small-cell lung cancer based on normal tissue dose constraints: a feasibility study. Int J Radiat Oncol Biol Phys. 71(5):1394-401. [3] van Baardwijk et al. 2010; Mature results of an individualized radiation dose prescription study based on normal tissue constraints in stages I to III non-small-cell lung cancer. J Clin Oncol. 28(8):1380-6. [4] Hoffmann et al. 2012; Individualized dose prescription for hypofractionation in advanced non-small-cell lung cancer radiotherapy: an in silico trial. Int J Radiat Oncol Biol Phys. 83(5): 1596-602. [5] Defreane et al. 2017; Regional variability in radiation- induced lung damage can be predicted by baseline CT numbers. Radiother Oncol. 122(2):300-306.