AG Bauer: Translationale Sarkomforschung
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 (sebastian.bauer@uk-essen.de) and CC Dr. Thomas Mühlenberg (thomas.muehlenberg@uk-essen.de).
Funding
Learn more about our DFG funded project.
Funded by The David Foundation
Sarkomtour
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
Post-Doc
WTZ-F room 0.015
Dr. rer. nat.
Dawid Krzeciesa
Post-Doc
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
Nils Dieckmann
physician
Lisa Ebel
Mastertstudent
WTZ-F room 0.018
Alexandra Heidemann
Technical Assistance
WTZ-F room 0.018
Lennart Schardt
cand. med.
WTZ-F room 0.018
Susanne Skibbe
Technical Assistance
WTZ-F room 0.018
Alena Spieckermann, B.Sc.
Masterstudent
WTZ-F room 0.018
Yanosan Thavarasa
Mastertstudent
WTZ-F room 0.018
Dagmar Thyssen
Technical Assistance
WTZ-F room 0.018
Stephanie Wesemann, M.Sc.
Phd student
WTZ-F room 0.016
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
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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.
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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.
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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
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T Mühlenberg, J 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.
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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
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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
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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.
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Inhibitors to Overcome Secondary Mutations in the Stem Cell Factor Receptor KIT.
Kaitsiotou H, Keul M, Hardick J, Mühlenberg T, Ketzer 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.
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Indazole-Based Covalent Inhibitors To Target Drug-Resistant Epidermal Growth Factor Receptor.
Tomassi S, Lategahn J, Engel J, Keul M, Tumbrink HL, Ketzer J, Mühlenberg T, Baumann M, Schultz-Fademrecht C, Bauer S, Rauh D.
J Med Chem 2017 Mar 23;60(6):2361-2372
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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.
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Insight into the Inhibition of Drug-Resistant Mutants of the Receptor Tyrosine Kinase EGFR.
Engel J, Becker C, Lategahn J, Keul M, Ketzer J, Mühlenberg 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
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Falkenhorst J, Grunewald S, Mühlenberg 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.
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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
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Mühlenberg T, Grunewald 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.
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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.
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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.
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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.
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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.
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p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.
Henze J, Mühlenberg T, Simon 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.
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Therapeutic Potential of Mdm2 Inhibition in Malignant Germ Cell Tumours.
Bauer S, Mühlenberg T, Leahy M, Hoiczyk M, Gauler T, Schuler M, Looijenga L.
Eur Urol. 2010 Apr;57(4):679-87.
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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
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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.