Cancer Research - Europa

Keywords | Kinases | pediatric pancers | new drugs |
KidsCancerKinome
Selecting and validating drug targets
from the Human kinome for high risk
paediatric cancers
Summary
Selecting and validating drug targets from the human
kinome for high risk pediatric cancers. KidsCancerKinome
will make a comprehensive analysis of the human protein
kinase family. Protein kinases are already excellent targets
for many small inhibitory molecules and antibodies designed
for adult tumors.
Six aggressive childhood tumors (neuroblastoma, medulloblastoma,
rhabdomyosarcoma, osteosarcoma, Ewing tumor,
acute lymphocytic leukemia) will be addressed, which are
responsible for 50 % of childhood cancer deaths. Viral shRNA
libraries will be applied to test the entire human kinase gene
family for tumor-driving kinases in cell lines. They will subsequently
be analyzed for mutations and functional parameters
in large cohorts of tumor samples. siRNA mediated inactivation
in larger cell line panels will critically validate suitable
kinases as drug targets.
Novel kinase inhibitors being developed for adult oncology
will be tested for in vitro activity against the tumor-driving
kinases. When no inhibitor is available, a novel generation of
siRNA based nucleic acid drugs (LNAs) will be applied.
Successful compounds will be taken further to in vivo validation
in established xenograft models of the six childhood
tumor types.
Problem
Each year 15 000 European children are diagnosed with
cancer and 25 % die of this disease. Survivors frequently
suff er from late side-eff ects of current treatments regimes.
Translational research of childhood tumors to identify
molecular targets for novel generations drugs is therefore
urgently needed. In addition, novel targeted drugs currently
developed for adult tumors have to become available for
children. Indeed, the EU launched in 2007 a paediatric Medicines
Regulation to stimulate drug evaluation in children.
Nine European research centers devoted to molecularbiologic
and pharmacologic studies of childhood cancers
and two SMEs therefore engaged in the KidsCancerKinome
project.
BIOLOGY
Aim
The overall aim of the KidsCancerKinome project is to systematically
explore the human kinase family for targeted
therapy development for children with cancer can be broken
down in the following objectives.
• In silico analysis of the ITCC microarray database (in
which we established the expression profi les of
600 childhood tumours), for expression profi les of all
protein kinase family members. The expression patterns
will be used to prioritize the analyses of the protein
kinases.
• 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-specifi c
viral siRNA library and bar-coding-based read out
system.
• Screening of extended cell line panels of the six selected
tumour types for dependency on known cancer-related
protein kinases and the protein kinases identifi ed in
step 2, by single-kinase siRNA.
• Mutation analysis of ‘tumour-driving’ protein kinases
(identifi ed in steps 1-3) in series of paediatric tumour
samples.
• Analysis of large clinical series of tumour samples for
presence and activation status of protein kinases identifi
ed in step 1-3 by immunohistochemistry.
• In vitro testing of available small molecules for inhibition
of the protein kinases identifi ed in step 1-3.
• In vitro testing of LNA kinase inhibitors for protein kinases
identifi ed in step 1-3 for which no small molecule
drugs are available.
• Validation of selected small molecule and LNA kinase
inhibitors in nude mouse transplants of childhood
tumours.
• 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.
Expected results
KidsCancerKinome will contribute to a better understanding
of the unique pediatric tumor biology and to
the development of new drugs.
Potential applications
Identifi cation of new drugable targets and development
of new specifi c treatments for childhood malignancies.
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