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Synthetic viability of homologous recombination-deficient cancers

Total Cost €


EC-Contrib. €






 SYNVIA project word cloud

Explore the words cloud of the SYNVIA project. It provides you a very rough idea of what is the project "SYNVIA" about.

advantages    tumors    mimic    inactivation    viability    therapeutic    although    generate    drugs    dna    physiologically    cancer    closely    emerges    brca    innovative    molecular    cas    survival    deficient    genetic    death    revolutionizing    recombination    underlying    repair    convinced    breast    explore    models    mutations    last    hr    combination    drug    cancers    treatments    observe    generation    brca1    found    disseminated    sequencing    model    screens    situation    functional    patients    deadly    resistance    primary    options    mouse    brca2    therapy    human    opportunity    yield    synvia    chemotherapy    despite    organoid    reduces    defective    decades    tractable    genetically    crispr    tumor    synthetic    homologous    powerful    cultures    mechanisms    arise    3d    alterations    directed    engineered    synergizing    initial    reverse    cells    minimizes    gene    am    genome    vivo    poorly    examples    striking    anti    designing    circumvent    lack    disease    escape   

Project "SYNVIA" data sheet

The following table provides information about the project.


Organization address
city: BERN
postcode: 3012

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Switzerland [CH]
 Project website
 Total cost 1˙999˙437 €
 EC max contribution 1˙999˙437 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2015-CoG
 Funding Scheme ERC-COG
 Starting year 2016
 Duration (year-month-day) from 2016-07-01   to  2021-06-30


Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNIVERSITAET BERN CH (BERN) coordinator 1˙999˙437.00


 Project objective

Although various effective anti-cancer drug treatments have become available over the last decades, drug resistance remains the major cause of death of cancer patients. Striking examples are patients with tumors that are defective in DNA repair by homologous recombination (HR). Despite initial responses to cancer therapy, resistance of primary or disseminated tumors eventually emerges, which minimizes therapeutic options and greatly reduces survival. The molecular mechanisms underlying this therapy escape are often poorly understood.

In the SYNVIA project I will address the problem of therapy escape by using powerful genetically engineered mouse models for BRCA1- and BRCA2-deficient breast cancer, which closely mimic the human disease. Due to the BRCA inactivation, the tumors that arise lack HR-directed DNA repair. Similar to the situation in cancer patients, we observe that cancer cells in these models eventually escape the deadly effects of chemotherapy or novel targeted drugs. Thus, these resistance models provide a unique opportunity to explore therapy escape mechanisms.

I propose an approach that will take the in vivo analysis of therapy resistance mechanisms to a new level. By synergizing the advantages of next generation sequencing with functional genetic screens in tractable model systems, I will explore novel mechanisms that cause resistance of HR-deficient cancers by the loss of another gene (“synthetic viability”). I provide evidence that new mechanisms of resistance can be identified with this approach. In an innovative step, I will generate genome-wide alterations using the revolutionizing CRISPR/Cas technology. Mutations will also be introduced into 3D tumor organoid cultures, as we found that these are more physiologically relevant. I am convinced that the combination of these state-of-the-art approaches will yield highly useful information for designing effective approaches to circumvent or reverse therapy escape in human cancer patients.


year authors and title journal last update
List of publications.
2018 Sylvie M. Noordermeer, Salomé Adam, Dheva Setiaputra, Marco Barazas, Stephen J. Pettitt, Alexanda K. Ling, Michele Olivieri, Alejandro Álvarez-Quilón, Nathalie Moatti, Michal Zimmermann, Stefano Annunziato, Dragomir B. Krastev, Feifei Song, Inger Brandsma, Jessica Frankum, Rachel Brough, Alana Sherker, Sébastien Landry, Rachel K. Szilard, Meagan M. Munro, Andrea McEwan, Théo Goullet de Rugy, Zhen-Yuan Lin, Traver Hart, Jason Moffat, Anne-Claude Gingras, Alberto Martin, Haico van Attikum, Jos Jonkers, Christopher J. Lord, Sven Rottenberg, Daniel Durocher
The shieldin complex mediates 53BP1-dependent DNA repair
published pages: 117-121, ISSN: 0028-0836, DOI: 10.1038/s41586-018-0340-7
Nature 560/7716 2019-06-18
2016 Stefano Annunziato, Marco Barazas, Sven Rottenberg, Jos Jonkers
Genetic Dissection of Cancer Development, Therapy Response, and Resistance in Mouse Models of Breast Cancer
published pages: 141-150, ISSN: 0091-7451, DOI: 10.1101/sqb.2016.81.030924
Cold Spring Harbor Symposia on Quantitative Biology 81 2019-06-18
2018 Ewa Gogola, Alexandra A. Duarte, Julian R. de Ruiter, Wouter W. Wiegant, Jonas A. Schmid, Roebi de Bruijn, Dominic I. James, Sergi Guerrero Llobet, Daniel J. Vis, Stefano Annunziato, Bram van den Broek, Marco Barazas, Ariena Kersbergen, Marieke van de Ven, Madalena Tarsounas, Donald J. Ogilvie, Marcel van Vugt, Lodewyk F.A. Wessels, Jirina Bartkova, Irina Gromova, Miguel Andújar-Sánchez, Jiri Bartek, Massimo Lopes, Haico van Attikum, Piet Borst, Jos Jonkers, Sven Rottenberg
Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality
published pages: 1078-1093.e12, ISSN: 1535-6108, DOI: 10.1016/j.ccell.2018.05.008
Cancer Cell 33/6 2019-06-18
2018 Nora M. Gerhards, Vincent A. Blomen, Merve Mutlu, Joppe Nieuwenhuis, Denise Howald, Charlotte Guyader, Jos Jonkers, Thijn R. Brummelkamp, Sven Rottenberg
Haploid genetic screens identify genetic vulnerabilities to microtubule-targeting agents
published pages: 953-971, ISSN: 1574-7891, DOI: 10.1002/1878-0261.12307
Molecular Oncology 12/6 2019-06-18
2018 Nora M. Gerhards, Sven Rottenberg
New tools for old drugs: Functional genetic screens to optimize current chemotherapy
published pages: 30-46, ISSN: 1368-7646, DOI: 10.1016/j.drup.2018.01.001
Drug Resistance Updates 36 2019-06-18
2018 Marco Barazas, Stefano Annunziato, Stephen J. Pettitt, Inge de Krijger, Hind Ghezraoui, Stefan J. Roobol, Catrin Lutz, Jessica Frankum, Fei Fei Song, Rachel Brough, Bastiaan Evers, Ewa Gogola, Jinhyuk Bhin, Marieke van de Ven, Dik C. van Gent, Jacqueline J.L. Jacobs, Ross Chapman, Christopher J. Lord, Jos Jonkers, Sven Rottenberg
The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells
published pages: 2107-2118, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2018.04.046
Cell Reports 23/7 2019-06-18
2017 Marina Pajic, Sohvi Blatter, Charlotte Guyader, Maaike Gonggrijp, Ariena Kersbergen, Aslι Küçükosmanoğlu, Wendy Sol, Rinske Drost, Jos Jonkers, Piet Borst, Sven Rottenberg
Selected Alkylating Agents Can Overcome Drug Tolerance of G 0 -like Tumor Cells and Eradicate BRCA1-Deficient Mammary Tumors in Mice
published pages: 7020-7033, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-17-1279
Clinical Cancer Research 23/22 2019-06-18
2017 Pepijn M. Schoonen, Francien Talens, Colin Stok, Ewa Gogola, Anne Margriet Heijink, Peter Bouwman, Floris Foijer, Madalena Tarsounas, Sohvi Blatter, Jos Jonkers, Sven Rottenberg, Marcel A. T. M. van Vugt
Progression through mitosis promotes PARP inhibitor-induced cytotoxicity in homologous recombination-deficient cancer cells
published pages: 15981, ISSN: 2041-1723, DOI: 10.1038/ncomms15981
Nature Communications 8 2019-06-18
2018 Marco Barazas, Alessia Gasparini, Yike Huang, Asli Küçükosmanoğlu, Stefano Annunziato, Peter Bouwman, Wendy Sol, Ariena Kersbergen, Natalie Proost, Renske de Korte-Grimmerink, Marieke van de Ven, Jos Jonkers, Gerben R Borst, Sven Rottenberg
Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors
published pages: canres.2077.2018, ISSN: 0008-5472, DOI: 10.1158/0008-5472.can-18-2077
Cancer Research 2019-04-17
2018 Paola Francica, Sven Rottenberg
Mechanisms of PARP inhibitor resistance in cancer and insights into the DNA damage response
published pages: , ISSN: 1756-994X, DOI: 10.1186/s13073-018-0612-8
Genome Medicine 10/1 2019-04-17
2018 Jordan R. Becker, Raquel Cuella-Martin, Marco Barazas, Rui Liu, Catarina Oliveira, Antony W. Oliver, Kirstin Bilham, Abbey B. Holt, Andrew N. Blackford, Jörg Heierhorst, Jos Jonkers, Sven Rottenberg, J. Ross Chapman
The ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity
published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-018-07855-x
Nature Communications 9/1 2019-04-17

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