Our website uses cookies. We use cookies to remember settings and to help provide you with the best experience we can. We also use cookies to continuously improve our website by compiling visitor statistics. Read more about cookies

 

Molenaar group

The Molenaar group aims at establishing a personalized treatment for every pediatric cancer patient. We do this by connecting basic biological research to targeted therapies which feeds our precision medicine program. Our translational work has a strong focus on neuroblastoma tumors.

PI: Dr. Jan Molenaar
Telefoon +31 6 18051678
"Every child its own treatment" Dr. Jan Molenaar - PI
The iTHER program

The goal of the iTHER (individualized THERapy) program is to realize personalized treatment for children with relapsed or refractory, incurable cancer. This involves 150 patients per year. The program is a METC approved clinical registry trial which is performed in collaboration with the group of Michel Zwaan. Molecular characterization includes low coverage Whole Genome Sequencing, Whole Exome Sequencing, RNAseq, an Affymetrix 133plus2 array and methylation pattern analysis using the DKFZ INFORM pipeline. Data is stored at the core facility of the Maxima and analyzed using the R2 bioinformatic platform. We have obtained an NWO precision medicine grant to further develop the iTHER program, which involves, clinical implementation of this program in the Maxima, connecting the program to targeted therapies and expanding our profiling with in vitro compound testing on patient derived tumor organoids.

Personalized cancer models

Tumors organoids from several pediatric tumor types, can now be adequately cultured. For neuroblastoma organoids the efficacy was only 50% and growth rates were low. To optimize this, we are currently systematically testing a repository of components of growth factors, pathway activating or inactivating components and various growth matrices and co-culture methods. Phenotyping is performing using single cell RNAseq on tumor biopsies and organoids. The organoids are subsequently used for automatic testing of a large compound library using robotics in a high-throughput set-up to identify optimal combination treatment options. These combination treatment options can be tested in in vivo models (PDX/GEMMS) that will be generated through an IMI2 funded program.

Target identification and validation in neuroblastoma

A highly efficient pipeline covering the full spectrum of targeted drug development is currently functional for neuroblastoma. The process starts with the identification of targets by mining high throughput data from Affymetrix mRNA profiling, RNAseq, Whole Genome Sequencing and single cell analysis. Potential new target genes are subsequently validated in in vitro systems using a variety of molecular genetic manipulation techniques. The most promising target genes are then further validated using small molecule inhibitors in vitro and in vivo. Several new models are developed to consolidate this process. Tumor organoids are used and new in vivo xenograft and transgenic models are implemented. The current studies are in various stages of development and involve BCL2, MDM2, CDK4/6, CDKN2A, the MEK pathway, ATRX and the 8 oxo-guanine repair pathway.

 

Members of the Molenaar group