- Bundesministerium für Bildung und Forschung KMU innovativ(BMBF): Biotechnologie BioChance
- Projektträger Jülich (PTJ)
Innovative tumour therapeutics specifically inhibit individual target structures. Protein kinases represent one of the largest enzyme classes currently pursued as drug discovery targets. However, actually for most kinase inhibitors there are no specific biomarkers available which provide a deeper understanding of the target activity and mechanism of action. In cooperation with ProQinase and Proteome Sciences the NMI identifies biomarkers to establish new test systems for the estimation of target inhibition and the biological effect. In future, these novel biomarker tests shall improve the development of targeted therapies against prostate carcinoma.
Today, in tumour therapy specific molecular targets are blocked by individual drugs. For pre-clinical and clinical tests the effective inhibition of the addressed targets leading to impaired tumour growth, is essential for the decision, whether the development of a substance or a specific therapy is continued. Due to the high burden for patients (e.g. periodic biopsies) direct analysis of primary tumours is not possible. Therefore, it is preferable to determine so called surrogate parameters in form of quantifiable biomarkers from blood samples. In this process, quantity or activity of a biomarker should be directly linked to target inhibition (target-specific biomarker) or the clinical phenotype induced by target inhibition (phenotypical biomarker).
Protein kinases are the most commonly addressed pharmacological targets in oncology. Currently, the lack of biomarkers for the majority of the oncologically relevant protein kinases is the biggest obstacle in drug development. Hence, early estimation of the efficiency and elucidation of the mode of action of a specific protein kinase inhibitor in pre-clinical and early clinical studies as well as in later clinical application is often precluded.
Aim of the project is the identification of new blood or serum biomarkers for the target-protein kinase cMet in prostate carcinoma. Subsequently, new test systems for the validation in patients should be established. Moreover, using RNA interference methods, inducible cell systems as well as murine tumour models will be assembled. Mass spectrometric methods allow sample analysis from cell systems and identify differentially expressed proteins and peptides as primary biomarker candidates. Using quantitative, specific mass spectrometric tests these biomarkers will be validated in blood samples from tumour-bearing mice with activated or inactivated targets, respectively. In addition, a kinome-wide siRNA screen is performed to identify new targets and biomarkers.
- Proteome Sciences