Analyse der Zellulären Signaltransduktion

Analyse der Zellulären Signaltransduktion
Untersuchung von Tumorproben

Untersuchung von Tumorproben
Bestrahlung von Zellkulturen mit Röntgenstrahlung

Bestrahlung von Zellkulturen mit Röntgenstrahlung

Signal Transduction & Molecular Targeting

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PD Dr. Malte Kriegs, Dipl.-Biochem.
Dr. Thorsten Rieckmann, Dipl.-Biol.
Dr. Nina Struve, Dipl. Biochem.
Dr. Lara Bußmann, HNO-Ärztin
Fruzsina Gatzemeier, MTA
Konstantin Hoffer, MTA
Lena Nordquist, MTA
M.Sc. Lisa Gleißner, PhD Stud.
Kaweh Beizaei, Stud. Med.
Justus Müller-Goebel, Stud. Med
Franziska Mau, BSc. Stud.
Tatjana Möller, BTA-Schülerin

Topic 1 — Targeting of head & neck squamous cell carcinoma (HNSCC)

The aim of this project is to target HNSCC cells to achieve better tumor control after X-irradiation. HNSCC tumors are characterized by frequent alterations in pro-survival signal cascades such as EGFR-Signaling. Because these alterations are associated with therapy resistance we focus on i) the better characterization of HNSCC cells and tumors in regard to cellular signaling and ii) the inhibition of aberrant activated signal cascades to increase radiosensitivity. Currently we investigate the effectivity of anti-EGFR strategies and the multikinase inhibitors sorafenib and regorafenib.

Fig. 1
Fig. 1

Figure 1: Inhibition of EGFR-dependend signal transduction in different HNSCC cell lines using the clinically approved monoclonal antibody cetuximab or the clinically approved tyrosine kinase inhibitor erlotinib. (Western blot)

Selected recent papers

  • Kriegs M et al., Radiosensitization of HNSCC cells by EGFR inhibition depends on the induction of cell cycle arrests. Oncotarget, 2016, doi: 10.18632/oncotarget.9161.
  • Möckelmann N, et al., Effect of sorafenib on cisplatin-based chemoradiation in head and neck cancer cells. Oncotarget, 2016, 7(17):23542-23551.
  • Myllynen L, Kwiatkowski M, Gleißner L et al., Quantitative proteomics unveiled: Regulation of DNA double strand break repair by EGFR involves PARP1. Radiother Oncol, 2015, 116(3):423-30.
  • Kriegs M, Gurtner K, et al., Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest. Radiother Oncol, 2015, 115(1):120-7.
  • Möckelmann N et al., Molecular targeting in combination with platinum-based chemoradiotherapy in head and neck cancer treatment. Head Neck, 2015, doi: 10.1002/hed.24031.
  • Laban S*, Steinmeister L* et al., Sorafenib sensitizes head and neck squamous cell carcinoma cells to ionizing radiation. Radiother Oncol, 2013, 109(2):286-92.
  • Saker J et al., Inactivation of HNSCC cells by 90Y-labeled Cetuximab strictly depends on the number of induced DNA double strand breaks. J Nucl Med, 2013, 54(3):416-23.
  • Wang M et al., Inhibition of the EGFR sensitizes NSCLC cells to radiation and etoposide via DNA double-strand break inducible senescence. Cancer Res, 2011, 71(19):6261-9.
  • Myllynen L et al., In tumour cells regulation of DNA double strand break repair through EGF receptor involves both NHEJ and HR and is independent of p53 and K-Ras status. Radiother Oncol, 2011, 101(1):147-51.
  • Kasten-Pisula U et al., Cellular and tumor radiosensitivity is correlated to epidermal growth factor receptor protein expression level in tumors without EGFR amplification. Int J Radiat Oncol Biol Phys, 2011, 15; 80(4):1181-8.
  • Kriegs M et al.,The epidermal growth factor receptor modulates DNA double-strand break repair by regulating non-homologous end-joining. DNA Repair (Amst), 2010, 9:889-897.

Grants
BMBF, Erich und Gertud Roggenbuck-Stiftung, UCCH-Ein-Drittelstipendium Spierling-Stiftung

Topic 2 — Human papillomavirus (HPV) associated HNSCC

A subset of HNSCC is caused by infections with high risk types of HPV (human papillomavirus). These tumors are highly responsive to radiotherapy and radiochemotherapy. We aim to understand the molecular mechanisms responsible and to establish molecular targeting approaches for efficient radiosensitization in order to safely de-intensify treatment in this group of patients. Our results suggest that HPV-positive HNSCC cells possess an impaired DNA double-strand-break repair capacity and are susceptible to radiosensitization by inhibition of Chk1 and PARP.

Fig. 2
Fig. 2

Figure 2: Higher radiosensiti-vity of HPV-positive HNSCC cells lines compared to HPV-negative HNSCC cell lines measured with colony formation assay. (Rieckmann et al. 2012)

Selected recent papers

  • Busch C-J et al., Similar cisplatin sensitivity of HPV-positive and -negative HNSCC cell lines. Oncotarget, 2016, doi: 10.18632/oncotarget.9028.
  • Güster et al., The inhibition of PARP but not EGFR results in the radiosensitization of HPV/p16-positive HNSCC cell lines. Radiother Oncol; 2014,13(3):345-51.
  • Busch CJ, Kriegs M, Laban S, Tribius S, Knecht R, Petersen C, Dikomey E, Rieckmann T. HPV-positive HNSCC cell lines but not primary human fibroblasts are radiosensitized by the inhibition of Chk1. Radiother Oncol; 2013, Sep, 108(3):495-9.
  • Rieckmann T, Tribius S, Grob TJ, Meyer F, Busch CJ, Petersen C, Dikomey E, Kriegs M. HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother Oncol; 2013, 107(2):242-6.

Grants
Stiftung Tumorforschung Kopf/Hals, Monika-Kutzner Stiftung

Topic 3 — Glioblastom & EGFRvIII

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adult patients with an estimated 5-year survival rate of less than 5%. Expression of the epidermal growth factor receptor variant III (EGFRvIII) is thought to be associated with therapy resistance and worse prognosis. To investigate the biology of EGFRvIII-expressing cells and to understand the impact of EGFRvIII expression on X-irradiation and chemotherapeutics we established a new cell culture model with isogenetic inherent EGFRvIII expression.

Fig. 3
Fig. 3

Figure 3: Detection of EGFRvIII in EGFRvIII negative U87MG and EGFRvIII expressing DKMG and BS153 GBM cells. (Confocal immune-fluorescence microscopy, 630x magnification)

Selected recent papers

  • Riedel M, Struve N et al., Sorafenib inhibits cell growth but fails to enhance radio- and chemosensitivity of glioblastoma cell lines. Oncotarget, accepted for publication
  • Struve N, Riedel M, Schulte A, Rieckmann T, Grob TJ, Gal A, Rothkamm K, Lamszus K, Petersen C, Dikomey E, Kriegs M. EGFRvIII does not affect cell growth, radiosensitivity or sensitivity against gefitinib in glioblastoma cells. Oncotarget; 2015; 6:33867-77.

Grants
Stadt Hamburg (Landesexzellenzinitiative, LEXI 2012)

Forschungsförderung der Medizinischen Fakultät der Universität Hamburg (FFM)

Brigitte und Dr. Konstanze Wegener Stiftung