© 2007
Freund/OncoLab
Group descripton
The
Children´s Cancer Research Institute (CCRI) is the largest centre for
research related to childhood cancer in Austria. The overall aim is to
improve the treatment options for children suffering from cancer. In
order to do so the institute interacts closely with its two spin-off
companies Trimed Biotech and LabDia, the St. Anna Children's Hospital
and other pediatric oncology hospitals and research institutions in
Austria, Europe and beyond.
The molecular biological laboratory, which accommodates 8 researchers,
has chosen Ewing´s sarcoma and related tumours to study the molecular
pathogenesis of cancer in children. These aggressive neoplasms, which
affect primarily bone and soft tissue, are clinically challenging
because of their high metastatic potential. The underlying genetic
aberrations in this disease serve as a paradigm for similar aberrations
in other types of cancers in children and adults.
Besides
tumour-specific mutations, we are investigating the function of genes
that contribute to a broad spectrum of different malignancies in
children and adults. We aim at characterising patterns of aberrant gene
expression that are associated with distinct courses of disease. Our
current studies seek to define the involvement of these genes in common
pathways of cell growth and death and to reveal molecular interactions
between them. Monitoring of prognostic patterns at diagnosis may allow
early stratification of therapy. In the long term, we hope to identify
novel targets for therapeutic intervention in Ewing´s sarcoma.
Our role in EET-Pipeline
The role of
the Molecular Biology Laboratory of the Children´s Cancer Research
Institute within this cluster project is to validate previously
identified cell cycle regulators as potential targets in Ewing´s sarcoma.
Specifically, the role of the MYC oncoprotein for Ewing´s sarcoma growth
and phenotype shall be defined and the consequences of pharmacological
and genetic MYC inhibition will be studied. We will develop tools to
interfere with MYC activity and define its share in the biology of the
disease. Ewing´s sarcoma is characterised by a specific and
rate-limiting gene rearrangement, EWS/FLI-1, which by unknown mechanisms,
regulates the expression of several cell cycle regulators including MYC. We will study the dependence of the EWS/FLI-1 oncogenic function on MYC
activity, thereby defining a hierarchical network of cell cycle
regulation in this disease. By closely interacting with the project
partners, parallels between gene networks in Ewing´s sarcoma and other
embryonal tumours will be defined which, eventually, will lead to the
identification of promising therapeutic targets.
This
research is expected make significant contributions to the aims of »EET-Pipeline«, which are the identification of druggable targets common
to embryonal tumours based on gene expression data and functional
studies.
Staff Member
Top 5 publications
1. Aryee DN, Kreppel M, Bachmaier R, Uren A, Muehlbacher K, Wagner S, Breiteneder H, Ban J, Toretsky JA, and Kovar H. Single-chain antibodies to the EWS NH(2) terminus structurally discriminate between intact and chimeric EWS in Ewing's sarcoma and interfere with the transcriptional activity of EWS in vivo. Cancer Res 2006;66:9862-9869.
2. Siligan C, Ban J, Bachmaier R, Spahn L, Kreppel M, Schaefer K-L, Poremba C, Aryee D, and Kovar H. EWS-FLI1 target genes recovered from Ewing´s sarcoma chromatin. Oncogene 2005;24:2512-2524.
3. Spahn L, Petermann R, Siligan C, Schmid JA, Aryee DN, and Kovar H. Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway. Cancer Res 2002;62:4583-4587.
4. Petermann R, Mossier BM, Aryee DN, Khazak V, Golemis EA, and Kovar H. Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II. Oncogene 1998;17:603-610.
5. Kovar H, Aryee DN, Jug G, Henockl C, Schemper M, Delattre O, Thomas G, and Gadner H. EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro. Cell Growth Differ 1996;7:429-437.