Ullrich, Roland - CAP 9

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).

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

Chatterjee, S., Heukamp, L. C., Siobal, M., Schottle, J., Wieczorek, C., Peifer, M., Frasca, D., Koker, M., Konig, K., Meder, L.,…, Ullrich RT* (2013). Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. J Clin Invest. *corresponding author

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 Mar 27. *corresponding author

Schöttle J, Chatterjee S, Volz C, Siobal M, Florin A, Rokitta D, Hinze Y,… Ullrich RT*. Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer. Oncotarget, 2015 *corresponding author

Sos, M.L.*, Fischer, S.*, Ullrich, R.*, Peifer, M.*, Heuckmann, J.M., Koker, M., Heynck, S., Stückrath, I., Weiss, J., Fischer, F., Michel, K., Goel, A., Regales, L., Politi, K.A., Perera, S., Getlik, M., Heukamp, L.C., Ansén, S., Zander, T., Beroukhim, R., Kashkar, H., Shokat, K.M., Sellers, W.R., Rauh, D., Orr, C., Hoeflich, K.P., Friedman, L., Wong, K.K., Pao, W., and Thomas, R.K. (2009). Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc Natl Acad Sci U S A, 106(43), 18351-18356. *shared first-authorship