E.E.T.-Pipeline

European Embryonal Tumor Pipeline

 

Overview

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© 2007

Freund/OncoLab

  

The group

Our main research focus is neuroblastoma, a common childhood tumor derived from primitive cells of the sympathetic nervous system. Treatment of neuroblastoma with polychemotherapy provokes good initial response, regardless of tumor stage. However, two major problems of the current treatment regimen exist. Disseminated stage 4 tumors frequently relapse due to minimal residual disease arising from a few resistant tumor cells, resulting in poor overall survival rates. On the other hand, overtreatment of biologically favorable localized tumors causes most of the surviving patients to suffer from significant organ toxicity, reducing their quality of life. Treatment of neuroblastoma still represents one of the greatest challenges in pediatric oncology, and novel therapeutic strategies are needed to improve this situation.
The wide range of clinical variability reflects the biological heterogeneity of neuroblastoma. Our major scientific aim is to acquire a comprehensive overview of the neuroblastoma biology underlying the malignant features as a prerequisite for the development of innovative, patient-tailored therapies. The resulting biological insights should serve as a model not only for other related embryonal tumors including medulloblastomas, nephroblastomas, hepatoblastomas and retinoblastomas but also for morphologically and biologically related small round blue cell tumors, such as lung carcinomas and melanomas. To achieve this goal, multiple projects are currently active in the lab. Within these projects we apply state-of-the-art high-throughput technologies allowing a global analysis of the genome, transcriptome and proteome in a large number of primary neuroblastomas and neuroblastoma cell culture models.
We also have a long-standing interest in the role of the Trk family of neurotrophin receptors in neuroblastoma tumorigenesis. High TrkA-expression is correlated with a favorable tumor biology and high overall survival, whereas TrkB is mainly expressed on unfavorable, aggressive neuroblastomas. Our lab has discovered that several genes involved in modulating therapy resistance, tumor invasion or angiogenesis are regulated via TrkA or TrkB signaling. The functional role of these genes in neuroblastoma cells is currently being investigated, and these genes are being evaluated for their potential as novel drug targets in neuroblastoma. (OncoLab Essen)

 

Our role in EET-Pipeline

Angelika Eggert is the project coordinator for the E.E.T-Pipeline strategic targeted research project. The project coordinating committee, including the scientific coordinator (A. Eggert) and the administrative coordinator (K. Astrahantseff) are responsible for the central project management and coordination of the project. We are also involved in research to identify and validate target proteins for novel diagnostic and therapeutic options. A number of genomics and proteomics platforms exists in our lab and will be utilized in this portion of the project, inlcuding application of Affymetrix-based technologies, the construction and use of tissue microarrays, mass spectrometric methods such as SELDI-MS serum profiling and the use of protein arrays to identify disease-specific and tumor subgroup-specific proteins in patient sera. Selected previously identified target genes and proteins will be preclinically validated as novel diagnostic and therapeutic options. Many groups have shown that miRNAs may play a role in cancer progression, and we have recently shown miRNAs to be disregulated in primary neuroblastomas and a cell culture model for amplified MYCN. We will take part in efforts to analyze miRNA expression in embryonal tumors within the E.E.T-Pipeline project to better define their role in tumorigenesis. A pipeline for preclinical testing of new agents for their applicability for embryonal tumors will be implemented within the E.E.T-Pipeline. We will take part in assessing a cMYC-inhibitor developed by NaPro BioTherapeutics, Inc. as proof-of-principle for implementing this pipeline. Proof-of-principle for the feasibility of efficient antibody development based on an identified target will also be assessed within the E.E.T-Pipeline. We will provide a possible therapeutic target for the development of a fully human antibody by an SME member of the consortium, Affitech.

 

Staff Member

 

Top 5 publications

1. Schulte JH, Horn S, Otto T, Samans B, Heukamp LC, Eilers U-C, Krause M, Astrahantseff K, Klein-Hitpass L, Buettner R, Schramm A, Christiansen H, Eilers M, Eggert A, Berwanger B. (2007) MYCN regulates oncogenic MicroRNAs in neuroblastoma. Int. J. Cancer 122: 699-704 (2008).

2. Schramm A, Vandesompele J, Schulte JH, Dreesmann S, Kaderali L, Brors B, Eils R, Speleman F, Eggert A. Translating expression profiling into a clinically feasible test to predict neuroblastoma outcome. Clin Cancer Res. 2007 Mar 1;13(5):1459-65.   

3. Schramm A, Schulte JH, Klein-Hitpass L, Havers W, Sieverts H, Berwanger B, Christiansen H, Warnat P, Brors B, Eils J, Eils R and Eggert A. (2005) Prediction of clinical outcome and biological characterization of neruoblastoma by expression profiling. Oncogene 24:7902-12.

4. Sitek B, Apostolov O, Stuhler K, Pfeiffer K, Meyer HE, Eggert A and Schramm A (2005) Identification of dynamic proteome changes upon ligand activation of Trk-receptors using two-dimensional fluorescence difference gel electrophoresis and mass spectrometry. Mol. Cell. Proteomics 4:291-9.

5. Schulte JH, Schramm A, Klein-Hitpass L, Klenk M, Wessels H, Hauffa BP, Eils J, Eils R, Brodeur GM, Schweigerer L, Havers W, Eggert, A (2005) Microarray analysis reveals differential gene expression patterns and regulation of single target genes contributing to the opposing phenotype of TrkA- and TrkB-expressing neuroblastomas. Oncogene 24: 165-77.