The overall purpose of the KidsCancerKinome is to explore on one hand the human kinome for targeted therapy in childhood cancer by analysing molecular biological characteristics of 6 paediatric malignancies and on the other hand to make new targeted anti-cancer compounds available for clinical use in children with cancer.
To reach our aim we have the following objectives :
1. In silico analysis of the ITCC microarray database (in which we established the expression profiles of 600 childhood tumours), for expression profiles of all protein kinase family members. The expression patterns will be used to prioritize the analyses of the protein kinases.
2. Functional high-throughput screening of the full >500 member kinase gene family for essential protein kinases in 24 childhood cancer cell lines, using a kinase-specific viral siRNA library and bar-coding-based read out system.
3. Screening of extended cell line panels of the six selected tumour types for dependency on known cancer-related protein kinases and the protein kinases identified in step 2, by single-kinase siRNA.
4. Mutation analysis of ‘tumour-driving’ protein kinases (identified in steps 1-3) in series of paediatric tumour samples.
5. Analysis of large clinical series of tumour samples for presence and activation status of protein kinases identified in step 1-3 by immunohistochemistry.
6. In vitro testing of available small molecules for inhibition of the protein kinases identified in step 1-3.
7. In vitro testing of LNA kinase inhibitors for protein kinases identified in step 1-3 for which no small molecule drugs are available.
8. Validation of selected small molecule and LNA kinase inhibitors in nude mouse transplants of childhood tumours.
9. Pharmacokinetic and pharmacodynamic studies of LNA’s for protein kinases selected in step 1-7 to identify LNA antagonist kinase inhibitor for the drug development pipeline of Santaris.
In order to achieve its targets the project is divided into several work package :
WP1 - Consortium Management
WP2 - Kinase expression patterns
WP3 - Kinome functional screening
WP4 - Kinase mutation analysis
WP5 - Kinase clinico-biological drug target validation
WP6 - Kinase Targeted Drug testing
WP7 - Kinase RNA antagonist (LNA) drug development