in vivo validated targets for diagnosis, treatment and prevention of JAK/STAT associated diseases
DKFZ Deutsches Krebsforschungszentrum
This technology relates to a screening method to identify new modulating compounds (small molecules, biologicals, etc.) for JAK/STAT associated diseases. The JAK/STAT signaling cascade represents an important pathway whose roles includes cell proliferation, haematopoiesis and immune response.
Inventors from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the Max-Planck-Institute for Biophysical Chemistry, Goettingen have developed a screening technology wherewith the activity of the Drosophila JAK/STAT signal transduction pathway can be measured in Drosophila Kc cells.
In order to identify novel pathway components and to widen classical genetic screens, the inventors have undertaken a genome-wide RNA interference (RNAi) screen and analysed 20,026 RNAi-induced phenotypes in cultured Drosophila melanogaster haemocyte-like cells.
With this screening technology the researchers have succeeded in identifying several genes with strong human homologues, which are associated with human malignancies. These new, in vivo validated targets enable the identification of JAK/STAT modulators for diagnosis, treatment and prevention of JAK/STAT associated diseases.
- Technology to identify new targets in the JAK/STAT pathway
- Method for identifying JAK/STAT-modulating compounds
- Several novel human targets of the JAK/STAT pathway associated with human diseases identified
Analysis of 20,026 RNA interference (RNAi)-induced phenotypes in cultured Drosophila melanogaster haemocyte-like cells identified interacting genes encoding 4 known and 86 previously uncharacterized proteins.
Subsequently, cell-based epistasis experiments were used to classify these proteins based on their interaction with known components of the signalling cascade. In addition to multiple human disease gene homologues, the inventors have found the tyrosine phosphatase Ptp61F and the Drosophila homologue of BRWD3, a bromo-domain-containing protein disrupted in leukaemia. Moreover, in vivo analysis demonstrates that disrupted dBRWD3 and overexpressed Ptp61F function as suppressors of leukaemia-like blood cell tumours.
Applications and Commercial Opportunity
The screen represents a comprehensive identification of novel loci required for JAK/STAT signalling and provides molecular insights into an important pathway relevant for human cancer. Human homologues of identified pathway modifiers may constitute targets for therapeutic interventions.
Michal Boutros (DKFZ), Martin Zeidler (MPI Göttingen), Patrick Müller (MPI Göttingen)
International PCT patent application published as WO2006/133931. Subsequent European (EP1910539) and USA (US-2009-0186815) equivalent filed. DKFZ is seeking for an industrial partner to license this technology or to collaborate with DKFZ.