Targeted therapy for BRAFV600E malignant astrocytoma

University of California, San Francisco, San Francisco, CA 94158, USA.
Clinical Cancer Research (Impact Factor: 8.72). 12/2011; 17(24):7595-604. DOI: 10.1158/1078-0432.CCR-11-1456
Source: PubMed


Malignant astrocytomas (MA) are aggressive central nervous system tumors with poor prognosis. Activating mutation of BRAF (BRAF(V600E)) has been reported in a subset of these tumors, especially in children. We have investigated the incidence of BRAF(V600E) in additional pediatric patient cohorts and examined the effects of BRAF blockade in preclinical models of BRAF(V600E) and wild-type BRAF MA.
BRAF(V600E) mutation status was examined in two pediatric MA patient cohorts. For functional studies, BRAF(V600E) MA cell lines were used to investigate the effects of BRAF shRNA knockdown in vitro, and to investigate BRAF pharmacologic inhibition in vitro and in vivo.
BRAF(V600E) mutations were identified in 11 and 10% of MAs from two distinct series of tumors (six of 58 cases total). BRAF was expressed in all MA cell lines examined, among which BRAF(V600E) was identified in four instances. Using the BRAF(V600E)-specific inhibitor PLX4720, pharmacologic blockade of BRAF revealed preferential antiproliferative activity against BRAF(V600E) mutant cells in vitro, in contrast to the use of shRNA-mediated knockdown of BRAF, which inhibited cell growth of glioma cell lines regardless of BRAF mutation status. Using orthotopic MA xenografts, we show that PLX4720 treatment decreases tumor growth and increases overall survival in mice-bearing BRAF(V600E) mutant xenografts, while being ineffective, and possibly tumor promoting, against xenografts with wild-type BRAF.
Our results indicate a 10% incidence of activating BRAF(V600E) among pediatric MAs. With regard to implications for therapy, our results support evaluation of BRAF(V600E)-specific inhibitors for treating BRAF(V600E) MA patients.

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Available from: Tim Forshew, Jul 01, 2014
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    • "KIAA1549:BRAF fusion positive pilocytic astrocytomas also occur less frequently with increasing age (164). Supratentorial tumors are less frequently fusion positive but have an increased frequency of the oncogenic BRAFV600E mutation (154), a putative pediatric low grade prognostic biomarker (165), and promising predictive biomarker (166). "
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    • "BRAF mutations have been found in a fraction of high-grade glioma patients (e.g. epitheloid GBM) and may present a druggable treatment target for specific inhibitors such as vemurafenib or dabrafenib[21], [22]. Another focus of interest is immunosuppressive molecules (e.g., B7H1 and B7H4); further research is warranted to define the role of immunomodulatory drugs in high-grade glioma[23]. "
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    • "This is of importance because BRAF and the MAPK pathway have been shown to have a key role in cerebellar development, with neural stem cells (NSCs) in this region demonstrating proliferation in response to expression of KIAA1549-BRAF, whereas NSCs in regions of the neocortex, for instance, do not (reviewed in [18,22]), paralleling incidence rates of KIAA1549-BRAF fusions detected in human tumors. These findings are being translated into clinical practice, as phase I/II clinical trials are currently assessing the benefit of using MAPK inhibitors in cases where adjuvant therapies are required [23]. In the context of low-grade diffuse astrocytoma, recent studies by Ramkissoon et al. have uncovered a chromosomal gain at 8q.13.1 in 28% of diffuse astrocytoma patients (grade II) that leads to a partial duplication of MYBL1 with a simultaneous truncation of its C-terminal negative regulatory domain [24]. "
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