PCLN-01. GENERATION, CHARACTERIZATION AND TREATMENT OF NOVEL MURINE MODELS FOR HUMAN PEDIATRIC GLIOMA. Issue 2 (22nd June 2018)

• Record Type: Journal Article
• Authors: Ismer, Britta; Moshe, Itai; Friedmann-Morvinski, Dinorah; Jones, David T W
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)supplement 2
• Page Start: i154
• Page End: i155
• Publication Date: 2018-06-22
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy059.570
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: In the last few years, the extent of heterogeneity between tumors of a given class has become increasingly evident. Thus, tumors should optimally be treated differently according to their individual genetic alterations. Within the ICGC PedBrain Tumor Project, we have analyzed >150 low-grade and high-grade pediatric gliomas with whole-genome DNA and RNA sequencing, and have identified a wide variety of genetic alterations responsible for tumor growth. This includes novel point mutations, fusions and duplications in oncogenes such as NTRK2, FGFR1 and ALK. In some cases these alterations also define distinct molecular subgroups of glioma as judged by DNA methylation profiling. In order to identify new targeted therapy options for pediatric gliomas, mouse models recapitulating the human disease are required for testing of more specific inhibitors. We have therefore generated a series of novel models which are now being characterized and pre-clinically treated. Initial results with ALK or NTRK fusions show that our somatic gene transfer methods (RCAS- or in utero electroporation-based) can be used to rapidly generate new orthotopic brain tumor models, and that specific inhibitors against chosen oncogenes have a greater effect on tumor growth compared to standard therapy. The murine tumor cells can also be cultivated as neurospheres for functional testing and e.g. high-throughput screens. In addition to the basic biological understanding of tumorigenic mechanisms that can now be elucidated in more detail, we aim to rapidly translate our pre-clinical results in a manner that we hope will directly benefit patients in the clinic.