Roland Ullrich - CAP 9

Targeting tumor angiogenesis

Introduction

In our group we are applying chemical genetics and in vivo approaches to investigate the molecular mechanisms that control the shift in the balance between anti- and pro-angiogenic factors; considered to switch tumor growth toward established tumors with autonomous blood supply. Herein, we seek to define genetically encrypted correlates of tumor angiogenesis that enables to decipher new molecular therapeutically tractable targets. Recently, we demonstrated that VEGFR2 is not only expressed on endothelial but also on tumor cells. We studied the function of VEGFR2 signaling in tumor cells and identified a tumor-cell autonomous VEGF-VEGFR2 feed-forward loop that induces an mTor dependent amplification of VEGF secretion (Chatterjee et al, JCI, 2013). These observations place the tumor cell-autonomous VEGF-VEGFR2 autocrine signaling loop in the mechanistic center of the “angiogenic switch” that has been postulated to control the development of blood vessel formation in tumors.

Approach

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.

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:

  • A: Deciphering synergistic therapeutic effects by combining anti-angiogenic therapy with molecular targeted therapy in lung cancer
  • B: Deciphering potential synergistic effects by combining immunotherapies
  • C: To identify and validate molecular signatures of lung cancer and lymphoma conferring response to immunotherapy

Selected publications

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. In press *corresponding author (IF 7,5)

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.
Cancer Res. 2018 [Epub ahead of print] *corresponding author (IF 9,3)

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, Schlößer HA, Odenthal M, Büttner R, Wolf J, Hallek M, Herling M, von Bergwelt-Baildon M, Reinhardt HC, Ullrich RT. (2018) LIN28B enhanced tumorigenesis in an autochthonous KRAS-G12V driven lung carcinoma mouse model.
Oncogene. 2018 May;37(20):2746-2756 (IF 7,5)

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. (IF 14,7)

Fernandez-Cuesta, L., Sun, R., Menon, R., George, J., Lorenz, S., Meza-Zepeda, L. A., Peifer, M., Plenker, D., Heuckmann, J. M., Leenders, F., ...Ullrich RT, et al. (2015). Identification of novel fusion genes in lung cancer using breakpoint assembly of transcriptome sequencing data. Genome biology 16, 7. (IF 10,8)

Schottle, J., Chatterjee, S., Volz, C., Siobal, M., Florin, A., Rokitta, D., Hinze, Y., Dietlein, F., Plenker, D., Konig, K., ... Ullrich, R.T. * (2015). Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer. Oncotarget 6, 38458-38468. *corresponding author (IF 6,4)

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. *corresponding author (IF 9,3)

Fernandez-Cuesta, L., Plenker, D., Osada, H., Sun, R., Menon, R., Leenders, F., Ortiz-Cuaran, S., Peifer, M., Bos, M., Dassler, J., … Ullrich RT, et al. (2014). CD74-NRG1 Fusions in Lung Adenocarcinoma. Cancer Discov. 4, 415-422. (IF 19,5)

Malchers F, Dietlein F, Schöttle J, Lu X, .., Ullrich RT, Reinhardt HC, Ringeisen F, Buttner R, Heukamp LC, Wolf J, Thomas RK. „Cell-autonomous and non-cell-autonomous mechanisms of transformation by amplified FGFR1 in lung cancer“. Cancer Discov. 2014 (IF 19,5)

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 (IF 13,3)

Sos, M. L., Dietlein, F., Peifer, M., Schottle, J., Balke-Want, H., Muller, C., Koker, M., Richters, A., Heynck, S., Malchers, F., et al. (2012). A framework for identification of actionable cancer genome dependencies in small cell lung cancer. Proceedings of the National Academy of Sciences of the United States of America 109, 17034-17039. (IF 9,7)

Heukamp, L. C., Thor, T., Schramm, A., De Preter, K., Kumps, C., De Wilde, B., Odersky, A., Peifer, M., Lindner, S., Spruessel, A., … Ullrich RT, et al. (2012). Targeted expression of mutated ALK induces neuroblastoma in transgenic mice. Sci Transl Med 4, 141ra191.
(IF 15,8)


PD Dr. Dr. Roland Ullrich

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

PD Dr. Dr. Roland Ullrich

Principal Investigator CAP 9

roland.ullrich@uk-koeln.de

Work +49 221 478 89771

Center for Molecular Medicine Cologne (CMMC)
Kerpener Str. 62
50937 Cologne

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

Publications

Link to PubMed

Group Members

Group Leader

  • PD Dr. Dr. Roland Ullrich (funded by NRW-NWG)

PostDocs

  • Lydia Meder (funded by NRW-NWG)
  • Sara Breidt (funded by Thyssen)
  • Sven Borchmann (funded by EKFS)

Lab-Management

  • Mirjam Koker (funded by NRW-NWG)

Technical Assistant

  • Marieke Nill

Medical student

  • Philipp Schuldt (funded by Koln Fortune)
  • Hanna Ludwig

Group alumni members since 2014

  • Sampurna Chatterjee, PhD
  • Alina Zaplatina, PhD
  • Caroline Volz, PhD
  • Kristina Golfmann, PhD
  • Gisela Schön
  • Sophie Neubert