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Univ.-Prof. Dr. med. Sebastian Bauer

Professorship for Translational Oncology / Personalized Tumortherapy

Medical Spokesperson Sarcomacenter Essen

 

CV (german)

PUBLONS  / ORCID

 

Dr. rer. medic. Thomas Mühlenberg

Head of the Laboratory

WTZ-F room 0.014

Email

+49 201 723 3150

PUBLONS  / ORCID

Dr. rer. nat. Susanne Grunewald

Post-Doc

WTZ-F room 0.015

Email

+49 201 723 85120

Julia Ketzer

Project Coordinator

WTZ-F room 0.014

Email

+49 201 723 85097

Miriam Christoff

Technical Assistance

WTZ-F room 0.015

Email

+49 201 723 85120

Dr. med. Johanna Falkenhorst

MD PhD  - UMEA - Clinician Scientist Program

Email

+49 201 723 - 85979

Dr. med. Rainer Hamacher

MD PhD - UMEA - Clincian Scientist Program

Email

+49 201 723 85031

Nils Dieckmann

cand. med. - Glückauf scholar

WTZ-F room 0.016

Email

 

Benjamin Fletcher, B.A.

Technical Assistance

Email

+49 201 723 3134

 

Yasmin Krausmüller, B.Sc.

Student Assistant

WTZ-F room 0.018

Email

 

Dawid Krzeciesa, M.Sc.

PhD student

WTZ-F room 0.016

Email

+49 201 723 3134

 

Lennart Schardt

cand.med. - Glückauf scholar

WTZ-F room 0.018

Email

  • 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.

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 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.

 

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 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.

 

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

 

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 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

 

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 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.

 

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 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.

 

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 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.

 

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. 

 

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.

Kontakt

Translational Sarcoma Research Group

University Hospital Essen

West German Cancer Center

WTZ-F R0.013

Hufelandstr. 55

45147 Essen

 

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).

+49 201 723 3150 +49 201 723 3112 E-Mail schreiben

SARKOMTOUR

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