ESTRO 36 Abstract Book

S229 ESTRO 36 _______________________________________________________________________________________________

for mCRPC. However, all patients with an DDR-associated ATM mutation failed therapy. A significant proportion of tumours harbour recurrent non-coding aberrations, important genomic rearrangements, and a novel mechanism of PTEN inactivation whereby a local inversion represses transcription of genes within its boundaries. Chromothripsis and kataegis is evident in one fifth of these tumours and can be associated with more aggressive disease. Using driver mutations, copy-number alterations and methylation, we were able to categorize patients into prognostic categories which has less than 5% or greater than 50% probability of relapse. The use of genomic markers as prognostic factors for local failure and for systemic disease are therefore novel risk-stratification tools which help to triage patients to existing treatment options, and potentially identification of molecular targets for therapy. However, our data also suggest that novel therapeutic approaches focus on recurrent non- mutation targets. This new approach could then prevent castrate-resistance by targeting genetic instability earlier on the natural history of the disease when fewer driver events are operational. OC-0436 Cytokine-dependent regulation of prostate cancer stem cell maintenance in response to irradiation C. Peitzsch 1,2 , M. Baumbach 1 , M. Cojoc 1 , L. Hein 1 , I. Kurth 1,2 , M. Baumann 1,2,3,4,5 , M. Krause 1,3,4,5 , A. Dubrovska 1,3,4 1 OncoRay - Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus- Technische Universität Dresden, Dresden, Germany 2 National Center for Tumor Diseases NCT, German Cancer Research Center DKFZ, Dresden, Germany 3 German Cancer Consortium DKTK, German Cancer Research Center DKFZ, Dresden, Germany 4 Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany 5 Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus- Technische Universität Dresden, Dresden, Germany Purpose or Objective According to the cancer stem cell hypothesis prostate cancer is driven by a malignant subpopulation with stem- like properties. These cancer stem cells (CSC) contribute to tumor-initiation, metastasis, therapy-resistance and tumor relapse. In parallel, genetic mutations accumulate over time and CSC subclones evolve. Therapeutic interventions like radiotherapy provide selective pressure for the expansion of resistant subclones with genetic diversification. We hypothesize that the determination of CSC-related biomarker in prostate cancer biopsies is correlating with clinical parameter and can be used for patient stratification and treatment selection to improve personalized radiotherapy. Material and Methods We generated isogenic radioresistant prostate cancer cell lines with a high expression of CSC marker, a epithelial- to-mesenchymal transition (EMT) phenotype, higher self- renewal properties, higher tumorigenicity and enhanced DNA repair capacity. We applied comparative genomic, proteomic, metabolomic, epigenomic and secretome analysis to identify novel biomarker for prostate cancer radioresistance and to unravel contributing molecular mechanisms. Novel biomarkers were validated using the Cancer Genome Atlas (TCGA) database and correlated with the tumor-free survival of prostate cancer patients after anti-cancer therapy including radiotherapy using SUMO software calculation. Results Within our first proof-of-principle study, we could show that ALDH-positive CSCs are radioresistant and maintained directly by the Wnt/β-catenin signaling pathway. In

Symposium with Proffered Papers: Novel approaches in prostate tumour control

SP-0434 State of the art in prostate tumour radiobiology C. Peitzsch 1,2 1 OncoRay - Center for Radiation Research in Oncology, University Hospital Carl Gustav Carus- Technische Universität Dresden, Dresden, Germany 2 Nationales Centrum for Tumor diseases NCT- Dresden, German Cancer Center DKFZ- Heidelberg, Dresden, Germany Prostate tumorigenesis is a multistep process from intraepithelial neoplasia (PIN) and localized adenocarcinoma, to castration-resistant prostate cancer (CRPC) and further into an invasive and metastatic disease stage with poor prognosis. Several driver and passenger mutations e.g. within the androgen receptor ( AR ), ETS , TP53 , PTEN , BRCA1/2, CTNNB1 or ATM were identified, so far, to be involved in this developmental process. Beside this specific genetic features of prostate cancer cells, cellular heterogeneity within prostate cancer describes the observation that malignant cells differ within their phenotypic features and functional properties. This tumor heterogeneity and cellular plasticity of tumor cells are the main driving forces for tumor growth, metastasis and therapy resistance and can be explained by the cancer stem cell (CSC) hypothesis in combination with clonal evolution and epigenetic regulation. CSC-specific molecular mechanisms of radioresistance mainly based on increased DNA repair capacity, enhanced reactive oxygen species (ROS) scavenging and induced epithelial- mesenchymal transition (EMT) and is regulated e.g. by the androgen-receptor signaling, the tumor microenvironment, growth factors and cytokines. Data from our own group indicating that ionizing radiation themself is modulating epigenetic mechanisms in prostate cancer cells and thereby cellular plasticity. To translate these basic research findings into clinically relevant data primary model systems and mouse models can be used for pre-clinical validation of radiosensitizer and biomarker discovery. SP-0435 Novel developments in molecular targeting of prostate cancer R. Bristow 1 1 Princess Margaret Cancer Centre University Health Network, Radiation Oncology - Room 5-964, Toronto, Canada Prostate cancer (CaP) remains the most common male malignancy worldwide. Although some localized cancers can be indolent, others can manifest aggressive biology with abnormal cancer metabolism and genetic instability. These men need intensified treatment to prevent metastatic castrate-resistant disease (mCRPC). Recent studies have started to define the genomic landscape of prostatic cancer heterogeneity in which mCRPC is associated with increasing androgen receptor aberrations, DNA repair deficiencies, mutations in PI3K and tumour suppressor gene pathways, aberrant WNT-beta-catenin signaling and defects in cell cycle control. For localized disease amenable to radiotherapy,we have previously shown that genetic instability and hypoxia are strong prognostic factors for prostate cancer outcome. Subsequently, we have gone on to analyze the whole- genomes and methylomes of 194 men and the exomes of 479 men to discover multimodal genetic signatures for responders and non-responders following precision radiotherapy and surgery. We observed that intermediate risk prostate cancers have a paucity of clinically- actionable mutations; in distinct contrast to that reported