GHS Richter

Klinikum rechts der Isar

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Stefan Burdach

Technical University of Munich

Martin S. Staege

Martin Luther University Halle-Wittenberg

Annette Fasan

ABX-CRO Advanced Pharmaceutical Services (Germany)

Oxana Schmidt

Klinikum rechts der Isar

Frauke Neff

München Klinik Harlaching

Julia Calzada‐Wack

Helmholtz Zentrum München

Kristina von Heyking

Technical University of Munich

Uwe Thiel

München Klinik Schwabing

Sabine Rössler

Technical University of Munich

Carsten Müller‐Tidow

University Hospital Heidelberg

Cooperative Institutions

Technical University of Munich

Klinikum rechts der Isar

Klinik und Poliklinik für Kinder- und Jugendmedizin

University Hospital Münster

German Cancer Research Center

Heidelberg University

University of Münster

Helmholtz Zentrum München

Heinrich Heine University Düsseldorf

Ludwig-Maximilians-Universität München

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420 Analysis of genomic alterations in Ewing sarcoma (German cohort) reveals cooperating mutations and novel therapy targets

European Journal of Cancer (2014)

GHS Richter Konstantin Agelopoulos Elizabeth Moreira dos Santos Schmidt Kristina von Heyking Barry Kurt Moser

10.1016/s0959-8049(14)70546-5

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Citations (1)

Characterization of HLA-A*0201 restricted cytotoxic CD8+ T cells directed against ewing tumor specific antigens

Klinische Pädiatrie (2009)

Stefan Pirson Uwe Thiel H. Bernhard GHS Richter Stefan Burdach

The rationale of adoptive T cell therapy is based on the attempt to circumvent pre-existing tolerance mechanisms by stimulating potentially tumor-reactive T cells ex vivo. Efforts to eradicate cancer by adoptive T cell transfer have been limited due to the difficulty of isolating tumor-reactive T cells present in low numbers in peripheral blood of tumor patients.

Adoptive Cell Transfer

10.1055/s-0029-1222667

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The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma

European Journal of Cancer (2016)

Kristina von Heyking Lea Roth Miriam Ertl Oxana Schmidt Julia Calzada‐Wack

Ewing's sarcoma

10.1016/s0959-8049(16)32726-5

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Citations (14)

Influence of Ewing tumor-specific genes for the chondro-osseous phenotype and localization of this malignancy

Klinische Pädiatrie (2009)

Kristina Hauer Annette Fasan GHS Richter Stefan Burdach

Ewing Tumors (ET) are highly malignant, localized in bone or soft tissue and are molecularly defined by ews/ets translocations. Our DNA microarray analysis revealed a relationship of ET to both endothelium and fetal neural crest but also identified several genes presumably important for chondro-osseous phenotype and differentiation of this tumor. Such genes are down-regulated by RNA interference in ET cell lines and their differentiation potential is investigated. Subsequently, ET lines with stable down-regulation of such genes generated by retroviral gene transfer of specific shRNA were established. Osseous tropism of these lines in immunodeficient Rag2-/-γC-/- mice is investigated. Initial results will be presented.

FLI1

10.1055/s-0029-1222643

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Vascular mimicry and neo-angiogenesis of Ewing Tumors explored based on the identification of angiogenetic target structures

Klinische Pädiatrie (2009)

Annette Fasan Sabine Rössler Diana Löwel Martin S. Staege GHS Richter

Aims: Metastatic spread in Ewing Tumors (ET) is hematogenous and malignant features have been shown to correlate with hypoxia and angiogenesis. We confirmed the endothelial signature by microarray analysis. This analysis revealed 37 genes that are highly up-regulated or even specifically expressed in ET including genes that may play a central role in angiogenesis of this tumor: Chondromodulin-1 (CHM1), a cartilage glycoprotein with anti-angiogenic activity, is believed to be involved in vasculogenic mimicry of tumor cells. G-protein coupled receptor-64 (GPR64) is an orphan receptor with normal expression restricted to human epididymis, is highly induced in ET. Methods used: The role of CHM1 and GPR64 expression in tumorigenicity and phenotype of Ewing Tumors was analyzed by RNA interference. Summary of results: Down-regulation of CHM1 and GPR64 in ET reduced their ability for contact independent growth in colony forming assays, while plastic adherent proliferation was not affected. Similarly, inhibition of GPR64 expression suppressed the ability of ET to constitute endothelial loops in tube forming assays whereas CHM1 knockdown even increased this capacity. CHM1 and even more GPR64 suppression in ET lines inhibited tumor development in immunodeficient Rag2-/-γC-/- mice. Subsequent microarray analysis of GPR64 knock down in ET revealed a GPR64-mediated regulation of genes with presumed central role in tumor specific angiogenesis. Conclusion: CHM1 and GPR64 up-regulation may shape ET angiogenesis and play a central role in the pathogenesis of this tumor.

Vasculogenic mimicry

10.1055/s-0029-1222634

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Human Leukocyte Antigen Distribution in German Caucasians with Advanced Ewing’s Sarcoma

Klinische Pädiatrie (2012)

Uwe Thiel Petra Wolf Angela Wawer Franziska Blaeschke Thomas G. P. Grünewald

Risk stratification criteria for patients with Ewing’s sarcoma family of tumors (ESFT) are still limited. We hypothesized divergent human leukocyte antigen (HLA) patterns in ESFT patients and compared HLA-A, -B and -DR phenotype frequencies of patients with advanced ESFT with those of healthy controls. HLA types of all German Caucasian patients with advanced ESFT and available HLA-A, -B and -DR data registered in the European Group for Blood and Marrow Transplantation, Paediatric Registry for Stem Cell Transplantation and the MetaEICESS data bases (study group, n=30) were retrospectively compared with HLA types of healthy German stem cell donors (control group, n=8 862 for single HLA frequencies and n=8 839 for allele combinations). Study group patients had been immuno-typed due to eligibility for allogeneic stem cell transplantation for high risk of treatment failure, and thus constituted a selected subgroup of ESFT patients. After Bonferroni correction for multiple testing (PC), phenotype frequencies of HLA-A24 remained significantly higher in the study group compared to controls (PC<0.05). Furthermore, several HLA combinations were significantly more frequent in the study group compared to controls (all PC<0.05). We report an increased incidence of circumscribed HLA patterns in German Caucasians with advanced ESFT. The possible clinical significance of this observation has to be re-assessed in prospective trials comprising larger ESFT patient numbers of all risk groups.

Clinical Significance

Histocompatibility

10.1055/s-0032-1321730

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Citations (2)

Inhibition of BET bromodomain proteins and the PI3K pathway in Ewing sarcoma down regulates the specific transcriptional program, inhibits tumorigenicity and increases apoptosis in Ewing sarcoma

European Journal of Cancer (2016)

Tim Hensel Chiara Giorgi Fiona Becker‐Dettling Julia Calzada‐Wack Frauke Neff

Ewing's sarcoma

Transcriptional activity

10.1016/s0959-8049(16)32727-7

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EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation

Klinische Pädiatrie (2009)

Stephanie Plehm Annette Fasan Sabine Rössler Rebekka Unland L Quintanilla-Martinez

Ewing Tumors (ET) are highly malignant, localized in bone or soft tissue and are molecularly defined by ews/ets translocations. DNA microarray analysis revealed a relationship of ET to both endothelium and fetal neural crest. We identified expression of histone methyl-transferase Enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be increased in ET. EZH2's suppressive activity maintains stemness in normal and malignant cells. Here, we found EWS/FLI1 bound to the EZH2 promoter in vivo and induced EZH2 expression in ET and mesenchymal stem cells. Down-regulation of EZH2 by RNA interference in ET suppressed oncogenic transformation by inhibiting clonogenicity in vitro. Similarly, tumor development and metastasis was suppressed in immunodeficient Rag2-/-γC-/- mice. EZH2-mediated gene silencing was shown to be dependent on histone deacetylase (HDAC) activity. Subsequent microarray analysis of EZH2 knock down, HDAC-inhibitor treatment and confirmation in independent assays revealed an undifferentiated phenotype maintained by EZH2 in ET. EZH2 regulated stemness genes such as nerve growth factor receptor (NGFR) as well as genes involved in neuroectodermal and endothelial differentiation (EMP1, EPHB2, GFAP, GAP43). These data suggest that EZH2 might play a central role in Ewing Tumor pathology by shaping the oncogenicity and stem cell phenotype of this tumor.

10.1055/s-0029-1222669

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Citations (5)

Transcriptome analysis of pediatric cALL versus normal tissue reveals a novel signature of the malignant phenotype

Klinische Pädiatrie (2009)

GHS Richter UE Hattenhorst Beate C. Beinvogl Daniel Schenk Martin S. Staege

Signature (topology)

10.1055/s-0029-1222674

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