Poster Presentation Advances in Neuroblastoma Research Congress 2016

ITCC Biology: pre-clinical targeted drug development for high-risk pediatric cancers (#287)

Emmy Dolman 1 , Bianca Koopmans 1 , Danny A. Zwijnenburg 1 , Huib C. Caron 2 , Monique L. den Boer 3 , Arnauld C. Verschuur 2 , Jan Koster 1 , Jan J. Molenaar 4 , the ITCC consortium 5
  1. Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  2. Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  3. Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands
  4. Department of Translational Medicine, Prinses Maxima Center for Pediatric Oncology, Utrecht, the Netherlands
  5. Contact person: Gilles Vassal, Direction of Clinical and Translational Research , Cancer Institute Gustave-Roussy, 114 rue Edouard Vaillant, 94805 Villejuif Cedex, Paris, France

Background

            The European consortium Innovative Therapies for Children with Cancer (ITCC) has been created in 2003 and aims to develop novel therapies for pediatric cancers. Within the consortium, ITCC Biology endeavours to supply the biological rationale for targeted drug trials in children with cancer. Therefore, a stepwise pipeline for the pre-clinical testing of targeted drugs across high-risk pediatric cancers has been set-up, from drug selection to in vivo evaluation. Currently, ITCC Biology focusses on opportunities for further expansion and development of the pre-clinical drug development pipeline.

 

Results

A robotic platform allowing high-throughput drug testing across multiple cell lines has been set-up. This platform has successfully been used to evaluate the in vitro efficacy of venetoclax, cobimetinib, binimetinib, selumetinib, trametinib, alectinib, crizotinib, LDK378, ribociclib, RG7388, TH588 and AT7519 in a panel of 32 cell lines representing 5 types of pediatric cancer, including neuroblastoma. IC50 and LC50 values were calculated using a novel developed analysis tool that is linked to the bioinformatics platform R2 (http://r2.amc.nl), thereby offering the possibility to directly correlate drug responses to genetic features. We were able to reproduce earlier findings in neuroblastoma cell lines, including correlations between sensitivity to MEK inhibitors and RAS-MAPK pathway mutations and between responses to MDM2 inhibition and p53 status. The same correlations could be found in other pediatric cancer types, such as rhabdomyosarcoma. Next screen will be performed using more compounds, including alectinib, pictilisib, taselisib, vemurafenib, ipatasertib, RG6016, RG7666, RG7741, RG7842, BCT-100, TH1579, TH1827 and JQ1, and will be finished within 6 months.

 

Conclusion

Proposed improvements in pre-clinical drug testing should eventually lead to more drugs entering clinical trials for neuroblastoma treatment and the faster discovery if drugs might also be useful for other pediatric cancers. The first screen clearly indicates that drug effects observed for neuroblastoma are comparable with effects obtained in other pediatric cancer types.