title: An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice.
abstract: Pilocytic astrocytoma (PA) is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. Children with incompletely resected PA represent a clinically challenging patient cohort for whom conventional adjuvant therapies are only moderately effective. This has produced high clinical demand for testing of new molecularly targeted treatments. However, the development of new therapeutics for PA has been hampered by the lack of an adequate in vivo tumor model. Recent studies have identified activation of MAPK signaling, mainly by oncogenic BRAF activation, as a hallmark genetic event in the pathogenesis of human PA. Using in vivo retroviral somatic gene transfer into mouse neural progenitor cells, we have shown here that ectopic expression of the activated BRAF kinase domain is sufficient to induce PA in mice. Further in vitro analyses demonstrated that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with the kinase inhibitor sorafenib. Our in vivo model for PA shows that the activated BRAF kinase domain is sufficient to induce PA and highlights its role as a potential therapeutic target.
authors.affiliation: Division Molecular Genetics (B060), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Gronych
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Josephine
authors.initials: J
authors.lastname: Bageritz
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.forename: Manfred
authors.initials: M
authors.lastname: Jugold
authors.forename: Dolores
authors.initials: D
authors.lastname: Hambardzumyan
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.forename: Sabine
authors.initials: S
authors.lastname: Heiland
authors.forename: Martin
authors.initials: M
authors.lastname: Bendszus
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001254:Astrocytoma / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001483:Base Sequence; D001932:Brain Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation; D018014:Gene Transfer Techniques; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D009857:Oncogenes; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf