Center for Molecular Medicine Cologne

Roland Ullrich - assoc. RG 23

Targeting tumor angiogenesis

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 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. Most strikingly, we found that combined inhibition of VEGFR2 and MAPK induces synergistic treatment effects in NSCLC that express VEGFR2 (see Figure 1).

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:

  1. Deciphering synergistic therapeutic effects by combining anti-angiogenic therapy with molecular targeted therapy in lung cancer
  2. Deciphering potential synergistic effects by combining anti-VEGF and PD-L1 targeted therapy
  3. To identify and validate molecular signatures of NSCLC cells conferring enhanced tumor cell invasion and metastasis

Selected publications

  1. Borchmann S, Cirillo S, Görgen M, Sasse S, Kreissl S, Bröckelmann P, von Tresckow B, Fuchs B, Diehl V, Ullrich RT*, Engert A*. Pre-Treatment Vitamin D Deficiency impairs progression free and overall Survival in Hodgkin Lymphoma and supplemental Vitamin D improves chemotoxicity in translational Hodgkin Lymphoma Models. J Clin Oncol 2019 Oct 17: *shared senior authorship
  2. 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, Buettner R, Wolf J, Hallek M, Herling M, von Bergwelt-Baildon M, Reinhardt HC, 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. 78, 4270–4281. *corresponding author
  3. 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
  4. Meder L, König K, Dietlein F, Macheleidt I, Florin A, Ercanoglu MS, Rommerscheidt-Fuss U, Koker M, Schön G, Odenthal M, Klein F, Büttner R, Schulte JH, Heukamp LC, Ullrich RT. (2018) LIN28B enhanced tumorigenesis in an autochthonous KRAS-G12V driven lung carcinoma mouse model. Oncogene. 2018 May;37(20):2746-2756
  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, et al. (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.
  6. Chatterjee, S., Wieczorek, C., Schottle, J., Siobal, M., Hinze, Y., Franz, T., Florin, A., Adamczak, J., Heukamp, L., Neumaier, B., Ullrich, RT * (2014). Transient anti-angiogenic treatment improves delivery of cytotoxic compounds and therapeutic outcome in lung cancer. Cancer Res. 2014 *corresponding author
  7. 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
  8. Sos, M. L.*, Fischer, S.*, Ullrich, RT*, 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
  9. Malchers F, Dietlein F, Schöttle J, Lu X, Nogova L, Albus K, Fernandez-Cuesta L, Heuckmann JM, Gautschi O, Diebold J, Plenker D, Gardizi M, Scheffler M, Bos M, Seidel D, Leenders F, Richters A, Peifer M, Florin A, Mainkar PS, Karre N, Chandrasekhar S, George J, Silling S, Rauh D, Zander T, 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
  10. Sos, M. L., Dietlein, F., Peifer, M., Schottle, J., Balke-Want, H., Muller, C., Koker, M., Richters, A., Heynck, S., Malchers, F. … Ullrich RT 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.
     

 

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

Co-Principal Investigator - B 02

CMMC - assoc. Research Group

 

+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

Curriculum Vitae (CV)

Publications

Link to PubMed

Group Members

Dr. Sven Borchmann    
Carolin Friederike Selenz    
Mirjam Koker    
Marieke Nill    
Christoph Otto    
Dr. Lydia Meder    
Anik Compes    
Dr. Philipp Gödel   

Figure 1