Research Focus

  • Analysis of oncogenetic signalling pathways in soft-tissue sarcomas (esp. GIST)
  • Evaluation of targeted small molecule kinase  inhibitors in soft-tissue sarcoma
  • Development of soft-tissue sarcoma models (cell lines and xenografts)
  • Evaluation of preclinical diagnostic techniques/methods for GIST and other soft-tissue sarcoma

Signalling pathways in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. More than 90% of all GISTs harbor activating mutations of the KIT and platelet-derived growth factor receptor A (PDGFRA) receptor tyrosine kinases, leading to malignant proliferation. Imatinib mesylate (IM / Gleevec), a small molecule inhibitor of KIT and PDGFRA is effective against the most common primary mutations. This leads in vitro and in vivo to an inhibition of proliferation and – to a limited extent – to apoptosis of GIST cells.

Clinically, the treatment with IM causes dramatic tumor reduction and long-term stabilisation of disease for more than 80% of patients with locally advanced or metastasized GIST. Complete remissions are rare and a substantial proportion of patients develops resistance to IM over time.

Apart from the 20% of all patients that display primary resistance to IM, the majority of patients initially responding to IM eventually develop a secondary resistance, associated with a dismal prognosis. Most patients then progress through 2nd to 4th line therapies within 1-2 years and salvage strategies are urgently needed. In most cases resistance is caused by secondary KIT mutations, preventing TKI binding. In later treatment lines a multitude of such resistance mutations can occur within the same patient, preventing efficent clinical control. In a few cases activation of alternative oncogenes or loss of crucial tumor supressors downstream of KIT occur.

Because of their exceptional genetic characteristics GIST represent a perfect model for examining the mechanism of action of tyrosine kinase inhibitors. Many other diseases exhibit similar oncogenetic mechanisms, e.g. the CML (BCR-ABL kinase), non-small-cell lung cancer (EGFR-Kinase) or Polycythemia vera (Jak-Kinase). Therefore, advances in understanding this model could also have therapeutical implications for other diseases.

The CRISPR/Cas9 Pipeline

GIST research has for long been hampered by a lack of representative disease models. Therfore, over the past years our group has implemented a CRISPR/Cas9-based model generation pipeline. This enables us to rapidly generate new models of mechanisms of resitance observed in the clinic.

Our group also focuses on the characterization of KIT-dependent signalling pathways in IM-sensitive and IM-resistant GIST cell lines, trying to identify alternative therapeutical targets. In collaboration with strong academic partners in chemical biology, we screen for or develop novel kinase inhibitors for GIST and other kinase driven cancers. We evaluate novel inhibitors in vitro and in vivo with the prospect of (short- to long-term) translation into clinical protocols.

Gene translocations/Fusion-driven Sarcomas

Apart from GIST the group also focuses on several other sarcoma types, driven by gene translocations. For example clear cell sarcomas and undifferentiated pleomorphic sarcomas are currently being investigated in consideration of other mechanism-based therapies.

Establishing new patient-derived cell lines

Sarcomas are rare and in itself diverse with about 150 subtypes. To meet the urgent need for reliable cell line models, another major focus of our group is the establishment of patient derived cell lines. In cooperation with the west german biobank (WBE), the departments of visceral and tumororthopedic surgery as well as the institute of pathology, we have established a process to collect and process fresh patient tumor tissue with the goal to create new, stable cell lines for various sarcoma subtypes.

Translational Sarcoma Research Group

University Hospital Essen
West German Cancer Center
WTZ-F R0.013
Hufelandstr. 55
45147 Essen

Tel.: 0201 723 3150

For inquiries regarding open Masterstudent, MD-thesis (lab) or PhD positions please send your CV and a short cover letter to Prof. Sebastian Bauer ( and CC Dr. Thomas Mühlenberg (


Logo Deutsche Forschungsgemeinschaft

Learn more about our DFG funded project.

Logo David foundation

Funded by The David Foundation


Learn about our annual fundraising bicycle tour that connects patients, physicians and researchers to promote and support sarcoma and GIST research.

Univ.-Prof. Dr. med.
Sebastian Bauer

Professorship for Translational Oncology / Personalized Tumortherapy Medical Spokesperson Sarcomacenter Essen

Dr. rer. medic.
Thomas Mühlenberg

Head of the Laboratory
WTZ-F room 0.014

Julia Ketzer

Project Coordinator
WTZ-F room 0.014

Dr. rer. nat.
Susanne Grunewald

WTZ-F room 0.015

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Dr. rer. nat.
Dawid Krzeciesa

WTZ-F room 0.016

Dr. med.
Johanna Falkenhorst

Fachärztin für Innere Medizin, Hämatologie und Onkologie
MD PhD – UMEA – Clinician Scientist Program

Miriam Christoff

Technical Assistance
WTZ-F room 0.015

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Nils Dieckmann


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Lisa Ebel

WTZ-F room 0.018

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Alexandra Heidemann

Technical Assistance
WTZ-F room 0.018

Lennart Schardt

cand. med.
WTZ-F room 0.018

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Susanne Skibbe

Technical Assistance
WTZ-F room 0.018

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Alena Spieckermann, B.Sc.

WTZ-F room 0.018

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Yanosan Thavarasa

WTZ-F room 0.018

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Dagmar Thyssen

Technical Assistance
WTZ-F room 0.018

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Stephanie Wesemann, M.Sc.

Phd student
WTZ-F room 0.016

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape

T Mühlenberg, J Falkenhorst, T Schulz, BS Fletcher, A Teuber, D Krzeciesa, I Klooster, M Lundberg, L Wilson, J Lategahn, M von Mehren, S Grunewald, AI Tüns, E Wardelmann, JK Sicklick, M Brahmi, C Serrano, H-U Schildhaus, S Sievers, J Treckmann, MC Heinrich, CP Raut, W-B Ou, A Marino-Enriquez, S George, D Rauh, JA Fletcher, S Bauer

J Clin Oncol. 2024 Feb 26:JCO2301197. doi: 10.1200/JCO.23.01197. Online ahead of print


Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA

A Teuber, T Schulz, BS Fletcher, R Gontla, T Mühlenberg, M-L Zischinsky, J Niggenaber, J Weisner, S B Kleinbölting, J Lategahn, S Sievers, M P Müller, S Bauer, D Rauh

Nat Commun. 2024 Jan 2;15(1):63. doi: 10.1038/s41467-023-44376-8.


Plasma Sequencing for Patients with GIST-Limitations and Opportunities in an Academic Setting

J Falkenhorst, S Grunewald, D Krzeciesa, T Herold, J Ketzer, M Christoff, R Hamacher, K Kostbade, J Treckmann, J Köster, F Farzaliyev, BS Fletcher, N Dieckmann, M Kaths, T Mühlenberg, HU Schildhaus, S Bauer

Cancers (Basel) 2022 Nov 9;14(22):5496. doi: 10.3390/cancers14225496.


Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain

S Grunewald*, L R Klug*, T Mühlenberg*, J Lategahn, J Falkenhorst, A Town, C Ehrt, E Wardelmann, W Hartmann, HU Schildhaus, J Treckmann, J A Fletcher, S Jung, P Czodrowski, S Miller, O Schmidt-Kittler, D Rauh, M C Heinrich*, S Bauer*

Cancer Discov. 2021 Jan;11(1):108-125. doi: 10.1158/2159-8290.CD-20-0487


KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors – TORC1/2 Inhibition as Salvage Strategy

T MühlenbergJ Ketzer, MC Heinrich, S Grunewald, A Marino-Enriquez, M Trautmann, W Hartmann, E Wardelmann, J Treckmann, K Worm, S Bertram, T Herold, HU Schildhaus, H Glimm, A Stenzinger, B Brors, P Horak, P Hohenberger, S Fröhling, JA Fletcher, S Bauer

Mol Cancer Ther. 2019 Nov;18(11):1985-1996. doi: 10.1158/1535-7163.MCT-18-1224.


Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours

Serrano C, Mariño-Enríquez A, Tao DL, Ketzer J, Eilers G, Zhu M, Yu C, Mannan AM, Rubin BP, Demetri GD Raut CP,  Presnell A, McKinley A, Heinrich MC, Czaplinski JT, Sicinska E, Bauer S, George S, Fletcher JA

Br J Cancer. 2019 Mar;120(6):612-620. doi: 10.1038/s41416-019-0389-6


Genomic aberrations in cell cycle genes predict progression of KIT-mutant gastrointestinal stromal tumors (GISTs).

Heinrich MC, Patterson J, Beadling C, Wang Y, Debiec-Rychter M, Dewaele B, Corless CL, Duensing A, Raut CP, Rubin B, Ordog T, van de Rijn M, Call J, Mühlenberg T, Fletcher JA, Bauer S.

Clin Sarcoma Res. 2019 Mar 5;9:3. doi: 10.1186/s13569-019-0112-7


Integrative genomic and transcriptomic analysis of leiomyosarcoma.

Chudasama P, Mughal SS, Sanders MA, Hübschmann D, Chung I, Deeg KI, Wong SH, Rabe S, Hlevnjak M, Zapatka M, Ernst A, Kleinheinz K, Schlesner M, Sieverling L, Klink B, Schröck E, Hoogenboezem RM, Kasper B, Heilig CE, Egerer G, Wolf S, von Kalle C, Eils R, Stenzinger A, Weichert W, Glimm H, Gröschel S, Kopp HG, Omlor G, Lehner B, Bauer S, Schimmack S, Ulrich A, Mechtersheimer G, Rippe K, Brors B, Hutter B, Renner M, Hohenberger P, Scholl C, Fröhling S.

Nat Commun. 2018 Jan 10;9(1):144.


Inhibitors to Overcome Secondary Mutations in the Stem Cell Factor Receptor KIT.

Kaitsiotou H, Keul M, Hardick J, Mühlenberg TKetzer J, Ehrt C, Krüll J, Medda F, Koch O, Giordanetto F, Bauer S, Rauh D.J

Med Chem. 2017 Nov 9;60(21):8801-8815.


Indazole-Based Covalent Inhibitors To Target Drug-Resistant Epidermal Growth Factor Receptor.

Tomassi S, Lategahn J, Engel J, Keul M, Tumbrink HL, Ketzer JMühlenberg T, Baumann M, Schultz-Fademrecht C, Bauer S, Rauh D.

J Med Chem 2017 Mar 23;60(6):2361-2372


MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation.

Schaefer IM, Wang Y, Liang CW, Bahri N, Quattrone A, Doyle L, Mariño-Enríquez A, Lauria A, Zhu M, Debiec-Rychter M, Grunewald S, Hechtman JF, Dufresne A, Antonescu CR, Beadling C, Sicinska ET, van de Rijn M, Demetri GD, Ladanyi M, Corless CL, Heinrich MC, Raut CP, Bauer S, Fletcher JA.

Nat Commun. 2017 Mar 8;8:14674.


Insight into the Inhibition of Drug-Resistant Mutants of the Receptor Tyrosine Kinase EGFR.

Engel J, Becker C, Lategahn J, Keul M, Ketzer JMühlenberg T, Kollipara L, Schultz-Fademrecht C, Zahedi RP, Bauer S, Rauh D.

Angew Chem Int Ed Engl. 2016 Aug 26;55(36):10909-12. doi: 10.1002/anie.201605011


Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib.

Falkenhorst J, Grunewald SMühlenberg T, Marino-Enriquez A, Reis AC, Corless C, Heinrich M, Treckmann J, Podleska LE, Schuler M, Fletcher JA, Bauer S.

Oncotarget. 2016 Jul 5;7(27):41390-41403. doi: 10.18632/oncotarget.9159.


Covalent-Allosteric Kinase Inhibitors  

Jörn Weisner, Rajesh Gontla, Leandi van der Westhuizen, Sebastian Oeck, Julia Ketzer, Petra Janning, Andre Richters, Thomas Mühlenberg, Zhizhou Fang, Abu Taher,Verena Jendrossek, Stephen C. Pelly, Sebastian Bauer, Willem A. L. van Otterlo, and Daniel Rauh

Angew Chem 2015 Jun 25; doi: 10.1002/anie.201502142


Inhibition of KIT-glycosylation by 2-deoxyglucose abrogates KIT-signaling and combination with ABT-263 synergistically induces apoptosis in gastrointestinal stromal tumor.  

Mühlenberg TGrunewald S, Treckmann J, Podleska L, Schuler M, Fletcher JA, Bauer S

PLoS One. 2015 Mar 17;10(3):e0120531. doi: 10.1371/journal.pone.0120531.


Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients.

Garner AP, Gozgit JM, Anjum R, Vodala S, Schrock A, Zhou T, Serrano C, Eilers G, Zhu M, Ketzer J, Wardwell S, Ning Y, Song Y, Kohlmann A, Wang F, Clackson T, Heinrich MC, Fletcher JA, Bauer S, Rivera VM.

Clin Cancer Res. 2014 Nov 15;20(22):5745-55. doi: 10.1158/1078-0432.


Phase I Study of Panobinostat and Imatinib in Patients with Treatment-Refractory Metastatic Gastrointestinal Stromal Tumors. 

Bauer S., Hilger R-A., Mühlenberg T., Grabellus F., Nagarajah J., Hoiczyk M., Reichardt A., Ahrens M., Reichardt P, Grunewald S., Scheulen M.E.,Pustowka A., Bock E., Schuler M., Pink D.

Brit J of Cancer. 2014 Jan;110(5):1155-62. doi: 10.1038/bjc.2013.826.


Targeting Gain of Function and Resistance Mutations in Abl and KIT by Hybrid Compound Design. 

Richters A, Ketzer J, Getlik M, Grütter C, Schneider R, Heuckmann JM, Heynck S, Sos ML, Gupta A, Unger A, Schultz-Fademrecht C, Thomas RK, Bauer S, Rauh D.

J Med Chem. 2013 Jul 25;56(14):5757-72.  


DOG1 regulates growth and IGFBP5 in gastrointestinal stromal tumors.

Simon S, Grabellus F, Ferrera L, Galietta LJ, Schwindenhammer B, Muehlenberg T, Taeger G, Eilers G, Treckmann J, Breitenbuecher F, Schuler M, Taguchi T, Fletcher JA, Bauer S.

Cancer Res. 2013 Jun 15;73(12):3661-70.


p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.

Henze J, Mühlenberg TSimon S, Grabellus F, Rubin B, Taeger G, Schuler M, Treckmann J, Debiec-Rychter M, Taguchi T, Fletcher JA, Bauer S.

PLoS One. 2012;7(5):e37776.


Therapeutic Potential of Mdm2 Inhibition in Malignant Germ Cell Tumours.

Bauer SMühlenberg T,   Leahy M, Hoiczyk M, Gauler T, Schuler M, Looijenga L. 

Eur Urol. 2010 Apr;57(4):679-87. 


Proapoptotic activity of bortezomib in gastrointestinal stromal tumor cells.

Bauer S, Parry JA, Mühlenberg T, Brown MF, Seneviratne D, Chatterjee P, Chin A, Rubin BP, Kuan SF, Fletcher JA, Duensing S, Duensing A.

Cancer Res. 2010 Jan 1;70(1):150-9. doi: 10.1158/0008-5472.CAN-09-1449


Inhibitors of deacetylases suppress oncogenic KIT signaling, acetylate HSP90, and induce apoptosis in gastrointestinal stromal tumors.

Mühlenberg T, Zhang Y, Wagner AJ, Grabellus F, Bradner J, Taeger G, Lang H, Taguchi T, Schuler M, Fletcher J, Bauer S

Cancer Res. 2009 Sep 1;69(17):6941-50.