Caspase modelling is a viable innovative tool in the precision medicine arsenal for stage III colorectal cancer (CRC)

EACR24 Poster Sessions / European Journal of Cancer 61, Suppl. 1 (2016) S9–S218 869 Ribosome biogenesis factors: novel clinical markers of breast cancer outcome F. Nguyen Van Long1 , N. Pion1 , A. Lardy-Cleaud2 , E. Lavergne2 , J.C. Bourdon3 , S. Chabaud2 , I. Treilleux4 , F. Catez1 , J.J. Diaz1 , V. Marcel1 . 1 ´ Centre de Recherche en Cancerologie de Lyon CRCL, Cancer Cell Plasticity, ´ ´ Lyon, France, 2 Centre Leon Berard, UBET, Lyon, France, 3 Jacqui Wood Cancer Center, Division of Cancer Research, Dundee, United Kingdom, 4 ´ ´ Centre Leon Berard, Translational Research, Lyon, France Ribosomes are the machinery translating messenger RNAs (mRNAs) into proteins. Ribosomes are ribozymes, which catalytic activity is carried out by ribosomal RNA (rRNA). rRNA undergoes chemical modifications, including 2 -O-ribose methylations (methylations) that are key for maintaining their ribozyme activity. Ribosome has a promising clinical value in cancer due to the fact that in cancer cells, ribosome biogenesis is increased. Novel therapies are developed to target factors involved in ribosome biogenesis that are also used as diagnostic and prognostic markers in cancers. For a long time, ribosome was seen as a unique entity that exhibits an unvariable translational activity. However, the notion of “specialized ribosomes” recently emerged involving that ribosomes present different compositions with specific translational activities. In particular, we showed for the first time that, in a mammary tumor initiation model, alterations of methylation impair the ribosome translational fidelity and translational initiation (Marcel et al., Cancer Cell, 2013). Indeed, modifications of rRNA methylations favor the IRES-dependent translation (Internal Ribosomes Entry Sites) of a subset of mRNAs coding for oncoproteins such as IGF1R and thus promote mammary tumorigenesis. These rRNA methylation alterations result from an increased expression of the unique rRNA methyl-transferase, the fibrillarin (FBL). The importance of ribosome methylations in mammary tumorigenesis was supported by the analyses of breast tumor samples. High mRNA level of FBL was significantly associated with poor overall and disease-free survivals. Moreover, multivariate analyses indicate that high level of FBL could be an independent marker of poor prognosis in breast cancer. Thus, FBL represents a potential prognosis marker of breast cancer. To firmly demonstrate that FBL is a clinical marker of breast cancer outcome, two different breast cancer series have been used. These two series were analyzed to determine whether FBL expression, at both mRNA and protein levels, is associated with breast cancer patients’ outcome. Series 1 is composed of 231 total RNA issued from breast tumor patients in which expression of FBL and 11 other genes involved in ribosome biogenesis were quantified by medium-throughput RT-qPCR in microfluidic system. Series 2 is composed of 440 breast tumor tissues in which FBL was stained by immunohistochemistry. Here, I will describe the technics and methodologies that have been developed to analyze these two series. Results will be described and discussed. Altogether, this study will support the use of ribosome biogenesis factors such as FBL as original clinical marker to improve breast cancer patients’ management. Moreover, it will support the role of ribosome in tumorigenesis and the usage of ribosome as a novel marker and targeted cancer therapy. No conflict of interest. 870 Caspase modelling is a viable innovative tool in the precision medicine arsenal for stage III colorectal cancer (CRC) M. Salvucci1 , M. Cremona1,2 , A. Lindner1 , A. Resler1 , E. Kay3 , B. Hennessy1,2 , P. Laurent-Puig4 , S. Van Schaeybroeck5 , M. Rehm1 , J. Prehn1 . 1 Royal College of Surgeons in Ireland RCSI, Physiology & Medical Physics Department, Dublin, Ireland, 2 Royal College of Surgeons in Ireland RCSI, Medical Oncology Department, Dublin, Ireland, 3 Beaumont Hospital, Pathology Department, Dublin, Ireland, 4 Universite´ Paris Descartes, UMR-S775 INSERM Laboratory, Paris, France, 5 Queen’s University Belfast, Centre for Cancer Research and Cell Biology, Belfast, United Kingdom Background: Response to chemotherapy, the current treatment paradigm in stage III CRC, is tightly linked to apoptosis susceptibility (AS). Thus, we applied a mathematical model of apoptosis signalling (APOPTO-CELL) and examined its translational potential, both on its own and in the context of other molecular and clinicopathological features (CPFs), as prognostic assay for stage III CRC patients. Materials and Methods: Patient-specific AS was simulated by APOPTOCELL in 3 cohorts: discovery cohort (in house multi-centre study, n = 120 (stage III)), validation cohort (TCGA colon adenocarcinoma, n = 136 (n = 39 stage III)) and expansion cohort (NCBI-GEO: GSE14333, GSE17538, GSE39582 and GSE41258, n = 978 (n = 353 stage III)) from the expression of procaspase-3 (PC3), procaspase-9, SMAC and XIAP. APOPTO-CELL inputs were determined by 1) RPPA; 2) RPPA (SMAC and XIAP) and RNASeq (PC3 and procaspase-9); and 3) gene profiling (Affymetrix) for the discovery, validation and expansion cohort, respectively. Random Forest (RF) machine learning was applied to identify the optimal relapse classifier (RFRC) from all the CPFs and molecular data available. Associations between modelling predictions and CPFs with disease-free survival (DFS) were analysed by Kaplan–Meier estimates and Cox proportional hazards regression models.

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Results: Patients predicted to be apoptosis-resistant had higher risk of recurrence (HR 2.05, 95% CI 1.03–4.05, p = 0.0415). Accounting for apoptosome-independent impact of PC3 by combining it with AS (AS+PC3) resulted in prognostic marker independent of other CPFs (p = 0.0371) with improved stratification respect to AS alone (+8.5% in Harrell’s concordance index). RFRC had a further improved prognostic accuracy over AS+PC3 (+9.4% in Harrell’s concordance index) with high risk patients having approximately 15 fold greater risk of relapse (HR 15.06, 95% CI 3.33– 68.08, p < 0.0001) compared to low risk patients. The prognostic signatures identified in the discovery cohort were independently validated in stage III TCGA COAD patients (logrank p = 0.0130, p = 0.0415 and p = 0.0401 for AS, AS+PC3 and RFRC, respectively). A differential role of AS was found in the CRC molecular subtypes CMS1−3 compared to CMS4 (interaction p = 0.0061) with the association between apoptosis-resistance and increased risk of recurrence being retained in CMS1−3 (HR 2.99, 95% CI 1.17–7.62, p = 0.0217), but not CMS4 (HR 0.22, 95% CI 0.03–1.74, p = 0.1503). A randomeffects meta-analysis showed that reduced AS (adjusted for CPFs) was associated with worse outcome (HR 1.74, 95% CI 1.20–2.53) in the expansion cohort, suggesting the suitability of gene expression profiling for caspase modelling. Conclusions: Apoptosis modelling is a clinically-validated appealing networkbased prognostic marker with a tangible prospect of portability into the clinical practise for the management of stage III CRC patients. Conflict of interest: Ownership: Jochen Prehn and Markus Rehm filed a patent on one of the mathematical analysis methods used in this study (“A computer-implemented system and method for the prediction of cancer response to genotoxic chemotherapy and personalised neoadjuvant treatments (pccp)”, Derwent primary accession number: 2013-A25393). 871 Proteomic profile in prostate cancer − From translational research to precision medicine C. Tanase1 , I.D. Popescu1 , E. Codrici1 , S. Mihai1 , A.M. Enciu1 , L. Necula1 , A. Preda2 , R. Albulescu3 . 1 Victor Babes National Institute of Pathology, Biochemistry-Proteomics, Bucharest, Romania, 2 Fundeni Clinical Institute, Center of Urological Surgery and Renal Transplantation, Bucharest, Romania, 3 National Institute for Chemical Pharmaceutical R&D, Pharmaceutical Biotechnology, Bucharest, Romania Introduction: Proteomic approaches are continuing to make headways in cancer research by helping to elucidate complex mechanism for new biomarkers that could be translated to clinical applications. Prostate cancer is the most common cancer in men and the second most frequent cause of cancer death. Material and Methods: Mass Spectrometry (SELDI-ToF MS) and twodimensional gel electrophoresis (2-DE) were used to perform the proteomic biomarkers profiling from 25 serum samples (15 prostate cancers and 10 controls). Results and Discussion: From the proteomic spectra (analyzed by SELDITOF), 20 significantly different expressed protein peaks were detected, with ROC-AUC values ranging 0.750–0.930 and p values lower than 0.01. The 2-DE comparative analysis of the protein profiles between prostate cancer and controls showed several differentially expressed proteins, results that confirm those obtained by SELDI-ToF-MS analysis. Biomarker Patterns Software (BPS) was applied to generate multiple biomarker correlation with clinical phenotype and accurate and reliable predictive models. Conclusion: Based on the two different proteomic approaches, a promising proteomic profile can be established, with potential application in translational medicine. Although the results appear to be encouraging, the biggest challenge about new markers in Prostate Cancer is to validate them in large clinical trials and subsequently implement these markers into clinical practice. Acknowledgment: Researches were supported supported by grants PN II 192/2014 and PN 16.22-04.01. No conflict of interest. 872 Effects of drugs active on tumor metabolism in head and neck paraganglioma cell lines R. Florio1 , L. De Lellis1 , V. Di Giacomo1 , M.L. Gallorini1 , A. Natale1 , M.C. Di Marcantonio2 , F. Verginelli1 , D. Verzilli1 , R. Mariani-Costantini2 , A. Cama1 . 1 University “G. d’Annunzio”, Department of Pharmacy, Chieti, Italy, 2 University “G. d’Annunzio”, Department of Medical- Oral and Biotechnological Sciences, Chieti, Italy Background: Head and neck paragangliomas (HN-PGLs) are relatively rare tumors that cause important morbidity. At present, surgery is the only therapeutic option for these chemo- and radio-resistant tumors. However, radical removal of HN-PGLs may be difficult or impossible because of their tendency to progressively infiltrate the skull base and vascular structures of the brain. Thus therapeutic molecules for HN-PGLs are highly needed. A high percentage of HN-PGLs are linked to germline mutations in succinate dehydrogenase genes (SDHx), encoding mitochondrial complex II subunits