Therapy Escape of Cancer

Prof. Dr. Sven Rottenberg, Direktor
Prof. Dr. Sven Rottenberg, Direktor

Cancer Therapy Resistance

Patients with tumors that are defective in DNA repair by homologous recombination (HR) are often sensitive to DNA-repair targeting agents. However, 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 mostly unclear.

In my group we are studying the basic mechanisms of therapy escape by using distinguished mouse models for BRCA1- or BRCA2-deficient breast cancer, which closely mimic the disease found in humans. Due to the BRCA inactivation, the tumors that arise lack HR-directed DNA repair; an Achilles heel that has provided a therapeutic opportunity to eradicate tumors with DNA damage-causing agents. However, similar to the situation in cancer patients, we observe that cancer cells in these models can escape the deadly effects of classical chemotherapy, novel targeted drugs or radiotherapy. Thus, these resistance models that we have established provide a unique opportunity to explore therapy escape mechanisms

Gruppenleiter

Mitarbeitende

5 ausgewählte Publikationen

  • Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Gogola et al. Cancer Cell 33: 1078-1093, 2018.
    This article shows that PARG depletion is a way for cancer cells to escape the deadly effects of PARP inhibition  without restoring homology-directed DNA repair.
  • BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance. Duarte, Gogola et al. Nat Methods, in press. doi: 10.1038/nmeth.4535.
    Here we describe the development of three-dimensional cancer organoids derived from BRCA1- and BRCA2-deficient mouse mammary tumors. These can be easily genetically modified, making them a powerful tool for genetic studies of tumor biology and drug resistance.
  • Selected alkylating agents can overcome drug tolerance of G0-like tumor cells and eradicate BRCA1-deficient mammary tumors in mice. Pajic, Blatter et al. Clin Cancer Res 23:7020-7033, 2017.
    In this article we demonstrate that targeting G0-like cells is crucial for the eradication of BRCA1/p53–deficient tumor cells. This can be achieved with selected alkylating agents such as nimustine.
  • Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. Planells-Cases et al. EMBO J 34:2993-3008, 2015.
    Here we show that about 50% of the cellular uptake of the frequently used anti-cancer drug cisplatin depends on LRRC8A and LRRC8D, which have recently been identified as subunits of the heteromeric LRRC8 volume-regulated anion channels (VRACs).
  • REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Xu et al. Nature 521:541-4, 2015.
    This article describes the identification of a new mechanism of drug resistance and provides novel insights into basic DNA repair mechanisms.

 

For a complete overview of the publications of the Rottenberg laboratory please see at ncbi.

CURRENT POSITION

  • 2017 –   Chair, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern
  • 2014 –   Director of the Institute of Animal Pathology, Vetsuisse Faculty, University of Bern

EDUCATION

  • 2004 Diploma of the European College of Veterinary Pathologists (ECVP)
  • 2003 PhD, Vetsuisse Faculty of the Universities Bern and Zürich, Switzerland
  • 2000 Doctor of Veterinary Medicine (DVM), University of Bern, Switzerland
  • 1997 Diploma (“Staatsexamen”) in Veterinary Medicine, Faculty of Veterinary Medicine, Free University of Berlin, Germany

PROFESSIONAL AND ACADEMIC EXPERIENCE

  • 2012 – 2014 Group leader (associate professor level), Molecular Oncology, The Netherlands Cancer Institute, Amsterdam
  • 2010 – 2012 Associate staff scientist, Molecular Biology, The Netherlands Cancer Institute, Amsterdam
  • 2007 – 2010 Senior postdoctoral fellow, Molecular Biology, The Netherlands Cancer Institute, Amsterdam
  • 2004 – 2007 Postdoctoral fellow, Molecular Biology, The Netherlands Cancer Institute, Amsterdam
  • 1999 – 2004 Resident in the combined Anatomic Veterinary Pathology/PhD program, Institute of Animal Pathology, University of Bern, Switzerland
  • 1998 – 1999 Resident in Domestic Animal Sciences, University of Kiel, Germany

INSTITUTIONAL RESPONSIBILITIES

  • 2017 –   Chair, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern
  • 2016 –   Faculty committee of the Vetsuisse Faculty, University of Bern
  • 2015 –   Chair, Comparative pathology platform (COMPATH) of the University of Bern
  • 2015 –   Experimental Animal Center Committee, University of Bern
  • 2014 –   Steering Committee Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern
  • 2014 –   Chair, Institute of Animal Pathology, Vetsuisse Faculty, University of Bern
  • 2011 – 2014 Laboratory Animal Committee of The Netherlands Cancer Institute, Amsterdam

MEMBERSHIPS IN SCIENTIFIC PANELS

  • 2017 –   Board of the Hans Sigrist Foundation
  • 2015 –   Expert committee “Molecular Biology & Biochemistry” of the Graduate School for Cellular and Biomedical Sciences, University of Bern
  • 2015 –   Working group “Non-human biobanks” (part of Swiss Biobanking Platform)
  • 2014 –   Clean Mouse Facility Kuratorium, University of Bern
  • 2007 – 2013 Exam Committee of the European College of Veterinary Pathologists (ECVP)

RESEARCH PROJECTS AS LEADING INVESTIGATOR

  • 2018 – 2022 Swiss Cancer League (KLS-4282-08-2017) Understanding the role of the CST complex in the synthetic lethal interaction between BRCA1 deficiency and PARP inhibition; CHF 330,000
  • 2016 – 2021 European Research Council (ERC) consolidator grant (681572): Synthetic viability of homologous recombination-deficient cancers (SYNVIA); EUR 2,000,000
  • 2015 – 2018 SNSF grant (310030_156869): Mechanisms of PARP inhibitor resistance of BRCA2-deficient mouse mammary tumors; CHF 505,302
  • 2012 – 2015 Dutch Cancer Society (NKI 2011–5220): Resistance to PARP inhibitors- association with DNA damage response alterations; EUR 533,300
  • 2011 – 2015 Netherlands Organization for Scientific Research VIDI (91711302): Predicting and targeting primary chemotherapy resistance in conditional mouse models of breast cancer; EUR 800,000

SUPERVISED PHD THESES (AS MAIN SUPERVISOR)

  • Ongoing: Christina Andronikou, Marco Barazas, Ewa Gogola, Martin Liptay, Merve Mutlu
  • 2018 Nora Gerhards: Exploring mechanisms of anti-cancer therapy response using haploid insertional mutagenesis screens
  • 2018 Sandra Huber (co-supervision with Kerry Woods): Protein interactions at the host-parasite interface in Theileria annulata-infected leukocytes
  • 2018 Sohvi Blatter: Targeting drug tolerance of residual Brca1-mutated mouse mammary tumors
  • 2016 Guotai Xu: Loss-of-function shRNA screens to identify mechanisms of PARP inhibitor resistance in BRCA1-mutated mouse mammary tumors
  • 2013 Janneke E Jaspers (co-supervision with Jos Jonkers): Targeting anti-cancer drug resistance mouse models of breast cancer
  • 2013 Serge AL Zander: Resistance to topoisomerase inhibitors in BRCA1-deficient mouse mammary tumors

SUPPORT OF RESEARCH FELLOWSHIPS OF YOUNG SCIENTISTS

  • 2014 –   Joana Santos Barbosa (Marie Skłodowska-Curie Action-Individual Fellowship, 2017-2019), Sohvi Blatter (SNSF MD-PhD program, 2014-2017), Martina Dettwiler (SNSF Doc Mobility, 2016), Natalia Domanitskaia (Marie Skłodowska-Curie Action-Training Network, 2015-2017), Nora Gerhards (SNSF Doc Mobility, 2015), Kerstin Hahn (SNSF Early Postdoc Mobility, 2018-2020), Martin Liptay (Boehringer Foundation, 2017-2019), Philipp Olias (SNSF Ambizione, 2017-2021), Kerry Woods (SNSF Ambizione, 2014-2018)

PRIZES, AWARDS

  • 2010 American Association for Cancer Research (AACR) – Translational Cancer Medicine Award
  • 2010 Best Poster Award, Annual Meeting on Cancer and Control of Genomic Integrity, Stockholm, Sweden
  • 2005 – 2007 Fellowship by the Swiss Foundation for Medical-Biological Grants (SSMBS, PASM33-108943) for the continuation of the study of multidrug resistance in Prof. Piet Borst’s group at the Netherlands Cancer Institute in Amsterdam)
  • 2004 – 2005 Fellowship by the Swiss National Science Foundation (PBBEB-104429) for the study of multidrug resistance in Prof. Piet Borst’s group at the Netherlands Cancer Institute in Amsterdam
  • 2003 Young Investigator Award of the American Society of Veterinary Pathologists (ASVP)
  • 2003 Swiss Society of Tropical Medicine and Parasitology Award 2003

(CO-) ORGANISATION OF CONFERENCES

  • 2017 EuroPOLA 2017 (Laboratory Animal Pathology), University of Bern
  • 2014 Preclinical Assays in Cancer Therapy, Curie Institute, Paris, France
  • 2012 Preclinical Assays in Cancer Therapy, Netherlands Cancer Institute, Amsterdam