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Forschung

Translational Sarcoma Research Group

Prof. Sebastian Bauer

Group leader

Susanne Grunewald

Dr. rer. nat.

Thomas Mühlenberg

Dr. rer. medic.

Julia Ketzer

Technician

Miriam Christoff

Technician

Dr. Susanne Grunewald

WTZ-F room 0.015

susanne.grunewald@uk-essen.de

+49 201 723 85120

 

Dr. Thomas Mühlenberg

WTZ-F room 0.014

thomas.muehlenberg@uk-essen.de

+49 201 723 3150

 

Julia Ketzer

WTZ-F room 0.014

julia.ketzer@uk-essen.de

+49 201 723 85097

 

Miriam Christoff

WTZ-F room 0.015

miriam.christoff@uk-essen.de

+49 201 723 85120

Johanna Falkenhorst

MD PhD

johanna.falkenhorst@uk-essen.de

 

Rainer Hamacher

MD PhD

rainer.hamacher@uk-essen.de

 

Annika Seis

PhD student

 

Kira Zierkowski

PhD student

 

Vivien Barein

PhD student

 

Valerie Haller

PhD student

 

Rebecca Boemans

PhD student

 

Janik Grothues

PhD student

 

Dawid Krzeciesa

Master student

 

 

  • Analysis of oncogenetic signalling pathways in soft-tissue sarcoma (esp. GIST)
  • Evaluation of purposive, small molecular inhibitors of tyrosine kinases in soft-tissue sarcoma
  • Development of soft-tissue sarcoma models (cell lines and Xenografts)
  • the evaluation of preclinical diagnostic techniques/methods (in vitro/in vivo) 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. Outstanding pathogenetic factors in more than 90% of all GISTs are activating mutations of the KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases that lead to uncontrollable proliferation. The imatinib mesylate (IM / Gleevec) small molecule inhibitor of KIT and PDGFRA biochemically represses the most important primary mutations. This leads in vitro as well as in vivo to an inhibition of proliferation and – in limited extent – to apoptosis of GIST cells.

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

 

Besides the 20% of all patients that have a primary resistance to IM, the majority of the patients that respond to IM eventually develop a secondary resistance that is associated with a dismal prognosis due to missing second-line-therapies. Secondary mutations of the ATP- (or rather Imatinib-)binding sites as well as amplification of KIT represent essential resistance mechanisms. In a few cases activation of alternative oncogenes occur.

 

Because of their exceptional genetic characteristics GIST tumours are notably suited as a simple model for the examination of the mechanism of action of tyrosine kinase inhibitors. Many other diseases exhibit similar oncogenetic mechanisms, e.g. the CML (BCR-ABL kinase), on-small-cell lung cancer (EGFR-Kinase) or Polycythemia vera (Jak-Kinase). Therefore gains of knowledge in this model could have therapeutical implication for other diseases.

 

Our work group also focuses on the characterization of KIT-depending signalling pathways in IM-sensitive and IM-resistant GIST cell lines, trying to identify alternative therapeutical target-proteins. We evaluate therapeutic-useable inhibitors preclinically with regard to a (short- to long-term) translation of those strategies into clinical protocols.

 

In addition several other sarcoma types are being evaluated in consideration of other mechanism-based therapies.

 

 

 

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

 

 

+49 201 723 3150 +49 201 723 3112

14. ESSENER SARKOMTOUR

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

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