Klin Padiatr 2012; 224 - A5
DOI: 10.1055/s-0032-1320173

Investigation of BRAF fusion genes as a therapeutic target in pilocytic astrocytoma

H Cin 1, J Gronych 2, 3, A Korshunov 4, DTW Jones 1, D Milford 5, T Milde 6, S Heiland 5, P Lichter 2, O Witt 6, SM Pfister 1, 7
  • 1Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 2Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 3Tumor Development Program, Sanford-Burnham Medical Research Institute, La Jolla, USA
  • 4Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 5Department of Neuroradiology, University Hospital Heidelberg, Germany
  • 6Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 7Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany

Pilocytic astrocytomas (PAs) are the most common pediatric brain tumors. Despite the benign clinical behavior reported for PA, treatment of tumors in critical anatomic locations remains challenging, since tumors often respond to conventional chemo and radiationtherapy poorly. BRAF fusion genes, rendering the MAPK pathway constitutively active, were shown to comprise a hallmark genetic event in PA thus suggesting a promising tumor-specific therapeutic target. This study aims at the in vivo and in vitro investigation of the pathogenic and therapeutic relevance of BRAF fusion genes in PA.

To model sporadic PA tumorigenesis, replication-competent avian leukosis virus with splice acceptor (RCAS) viral vectors containing FAM131B-BRAF and KIAA1549-BRAF fusion genes will be injected into the brain of newborn Nestin-Tv-a mice to express the BRAF fusion variants in neural progenitor cells. Further, primary murine Nestin-Tv-a astrocytes transduced with the BRAF fusion variants are currently being used for in vitro characterization.

The first in vivo model for PA generated in our group confirmed that the expression of a constitutively active BRAF kinase domain is sufficient to induce tumors in mice with clinical and biological patterns closely reflecting human PA.

As they are detected in more than 70% of PA, the in vivo characterization of BRAF fusion gene variants is of great clinical importance. This model represents an excellent tool to exploit molecular mechanisms underlying tumor initiation, progression and therapy response and will be used to assess the efficacy of novel therapeutic approaches, using specific BRAF and MEK1/2 targeted drugs. Ultrahighfield MRI imaging and histopathologic analysis will be conducted to evaluate tumor growth and response to treatment.

Utilizing somatic transfer of BRAF fusion genes as a tumor-initiating event, this in vivo model closely mimics human PA tumorigenesis, and will likely prove to be of great use for optimizing current therapies and for the development of novel therapy modalities in the future.