Center for Molecular Medicine Cologne

Roland Ullrich - CAP 9

Targeting tumor angiogenesis

We aim to define genetically encrypted correlates of tumor angiogenesis and tumor cell proliferation that enables to decipher new molecular therapeutically tractable targets. Another focus of our group are immunotherapeutic approaches and their combination with anti-angiogenetic treatment.

Introduction

The major challenge in battling the cancer problem is the fact that cancer is a collection of different, constantly evolving genetic diseases. During tumor development incipient cancer cells undergo a multistep mutational process, during which they acquire a set of genetic and/or epigenetic lesions, which ultimately result in the cancerous state. These mutations provide the cancer cell with a set of traits that have been termed the ‘hallmarks of cancer’ – potential for unlimited proliferation, mitogen-independence, escape from apoptotic signals, immune evasion, sustained angiogenesis, tissue invasion and ultimately metastasis (Hanahan and Weinberg, 2000). These cancer phenotypes are thought to be the consequence of gain of function of oncogenes or inactivation of tumor suppressor genes. Due to recent technological advances, such as next generation sequencing, we are beginning to understand the complex genetic changes that ultimately result in cancerous growth.

In our group we are applying chemical genetics and in vivoapproaches to investigate the molecular mechanisms that control tumor angiogenesis and tumor cell proliferation. Herein, we seek to define genetically encrypted correlates of tumor angiogenesis and tumor cell proliferation that enables to decipher new molecular therapeutically tractable targets. Another focus of our group are immunotherapeutic approaches and their combination with anti-angiogenetic treatment. We employ cell culture and syngeneic, autochthonous and other mouse models of various cancers such as lung cancer, breast cancer, lymphoma and sarcoma to study treatment combinations and mechanisms of actions and resistance. In doing so, we particularly focus on the effects of various treatment algorithms on the hosts immune system to decipher potential synergies with novel immunotherapies. We also aim to understand why only a minority of patients with certain cancers such as lung cancer respond to immunotherapy and why those that do respond become resistant to it. In the long term we hope to use synergistic, mechanistically plausible combination treatments together with immunotherapy to overcome these problems and translate our findings into patient care.

Perspectives

Our group aims to investigate the molecular mechanisms that regulate tumor angiogenesis. This knowledge in hand we will define new combined potentially synergistic drug combinations to improve response to targeted therapy. In detail we will address the following aims:

  • Deciphering synergistic therapeutic effects by combining immunotherapeutic approaches in lung cancer
  • Deciphering potential synergistic effects by combining anti-angiogenic targeted therapy with immunotherapeutic approaches 
  • To identify and validate molecular signatures of NSCLC cells conferring enhanced tumor cell invasion and metastasis
    1. Golfmann K, Meder L, Koker M, Volz C, Borchmann S, Tharun L, Dietlein F, Malchers F, Florin A, Büttner R, Rosen N, Rodrik-Outmezguine V, Hallek M, and Ullrich RT*. (2018) Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1 amplified breast cancer.Oncogene. 2018 Oct;37(42):5682-5693 *corresponding author 
    2. Meder L, Schuldt P, Thelen M, Schmitt A, Dietlein F, Wennhold K, Vlasic I, Oberbeck S, Riedel R, Florin A, Schlößer H, Odenthal M, Büttner R, Wolf J, Hallek M, Herling M, von Bergwelt-Baildon M, Reinhardt HC, and Ullrich RT*. (2018) Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. 
    3. Cancer Res. 2018 [Epub ahead of print] *corresponding author
    4. Chatterjee, S., Wieczorek, C., Schottle, J., Siobal, M., Hinze, Y., Franz, T., Florin, A., Adamczak, J., Heukamp, L., Neumaier, B., Ullrich, R. T. * (2014). Transient anti-angiogenic treatment improves delivery of cytotoxic compounds and therapeutic outcome in lung cancer.
      Cancer Res. 2014 *corresponding author (IF 9,3)
    5. Chatterjee, S., Heukamp, L. C., Siobal, M., Schottle, J., Wieczorek, C., Peifer, M., Frasca, D., Koker, M., Konig, K., Meder, L., et al., … Ullrich RT* (2013). Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer.
      J Clin Invest. *corresponding author 
    6. Sos, M. L.*, Fischer, S.*, Ullrich, R. T.*, Peifer, M. *, Heuckmann, J. M., Koker, M., Heynck, S., Stuckrath, I., Weiss, J., Fischer, F., et al. (2009). Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer.
      Proceedings of the National Academy of Sciences of the United States of America 106, 18351-18356.
      *equally contributed. 
    7. Mariappan A, Soni K, Schorpp K, Zhao F, Minakar A, Zheng X, Mandad S, Macheleidt I, Ramani A, Kubelka T, Dawidowski M, Golfmann K, Wason A, Yang C, Simons J, Schmalz HG, Hyman AA, Aneja R, Ullrich R, et al. 2019 Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells. EMBO J. 2019 Jan 15;38(2.
    8. Golfmann K, Meder L, Koker M, Volz C, Borchmann S, Tharun L, Dietlein F, Malchers F, Florin A, Büttner R, Rosen N, Rodrik-Outmezguine V, Hallek M, and Ullrich RT*. (2018) Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1 amplified breast cancer. Oncogene. 2018 Oct;37(42):5682-5693 *corresponding author 
    9. Zirkel A, Nikolic M, Sofiadis K, Mallm JP, Brackley CA, Gothe H, Drechsel O, Becker C, Altmüller J, Josipovic N, Georgomanolis T, Brant L, Franzen J, Koker M, Gusmao EG, Costa IG, Ullrich RT, Wagner W, Roukos V, Nürnberg P, Marenduzzo D, Rippe K, Papantonis A. (2018) HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types . Mol Cell. 2018 May 17;70(4):730-744.e6. 

    Mariappan, A., Soni, K., Schorpp, K., Zhao, F., Minakar, A., Zheng, X., Mandad, S., Macheleidt, I., Ramani, A., Kubelka, T., Dawidowski, M., Golfmann, K., Wason, A., Yang, C., Simons, J., Schmalz, H.G., Hyman, A.A., Aneja, R., Ullrich, R., Urlaub, H., Odenthal, M., Buttner, R., Li, H., Sattler, M., Hadian, K., and Gopalakrishnan, J. (2019). Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells. EMBO J 38.

    Golfmann K, Meder L, Koker M, Volz C, Borchmann S, Tharun L, Dietlein F, Malchers F, Florin A, Buttner R, Rosen N, Rodrik-Outmezguine V, Hallek M, and Ullrich RT (2018). Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1-amplified breast cancer. Oncogene 37, 5682-5693.

    Meder L, Konig K, Dietlein F, Macheleidt I, Florin A, Ercanoglu MS, Rommerscheidt-Fuss U, Koker M, Schon G, Odenthal M, Klein F, Buttner R, Schulte JH, Heukamp LC, and Ullrich RT (2018). LIN28B enhanced tumorigenesis in an autochthonous KRAS(G12V)-driven lung carcinoma mouse model. Oncogene 37, 2746-2756.

    Meder L, Schuldt P, Thelen M, Schmitt A, Dietlein F, Klein S, Borchmann S, Wennhold K, Vlasic I, Oberbeck S, Riedel R, Florin A, Golfmann K, Schlosser HA, Odenthal M, Buttner R, Wolf J, Hallek M, Herling M, von Bergwelt-Baildon M, Reinhardt HC, and Ullrich RT (2018). Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res 10.1158/0008-5472.CAN-17-2176.

    Zirkel A, Nikolic M, Sofiadis K, Mallm JP, Brackley CA, Gothe H, Drechsel O, Becker C, Altmuller J, Josipovic N, Georgomanolis T, Brant L, Franzen J, Koker M, Gusmao EG, Costa IG, Ullrich RT, Wagner W, Roukos V, Nurnberg P, Marenduzzo D, Rippe K, and Papantonis A (2018). HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types. Mol Cell 70, 730-744 e736.

    Univ.-Prof. Dr. med. Dr. nat. med. Roland Ullrich CMMC Cologne
    Univ.-Prof. Dr. med. Dr. nat. med. Roland Ullrich

    Dept. I of Internal Medicine / RG location - CMMC Building

    Principal Investigator CAP 9

    +49 221 478 89771

    +49 221 478 6882

    Dept. I of Internal Medicine / RG location - CMMC Building

    Kerpener Str. 62

    50937 Cologne

    http://innere1.uk-koeln.de/forschung/krebstherapie-und-molekulare-bildgebung

    CMMC Profile Page

    Publications

    Link to PubMed

    Group Members

    Lydia Meder, PhD, PostDoc 
    Sara Breid, PhD, PostDoc 
    Sven Borchmann, MD, PostDoc 
    Carolin Selenz, MSc, PhD-student 
    Marieke Nill, Technician 
    Mirjam Koker, BSc 
    Christoph Otto, MD student 
    Hanna Ludwig, MD student