The purpose of this study was to clarify the incidence of B-RAF mutations and their possible relation with tumor progression in a series of 82 human gliomas, including 49 astrocytic and 33 oligodendroglial tumors.
We now report that AAL881, a novel low-molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts.
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.
Tandem duplications involving the BRAF kinase gene have recently been identified as the most frequent genetic alteration in sporadic pediatric glioma, creating a novel fusion protein (f-BRAF) with increased BRAF activity.
In this report, we highlight advances in Nf1-GEM modeling and review new experimental evidence that supports the emerging concept that Nf1- and KIAA1549:BRAF-induced gliomas arise from specific cell types in particular brain locations.
One of our E-GBM patients with initial gross total resection quickly recurred within 4 months, required a second resection, and then was placed on vemurafenib; she remains tumor free 21 months after second resection without neuroimaging evidence of residual disease, adding to the growing number of reports of successful treatment of BRAF-mutated glial tumors with drug.
Development of selective inhibitors of BRAF has improved the survival of patients with melanoma and offers potential new therapeutic strategy in children with BRAF-mutant glioma.
The researchers have started a second trial for patients with glioma and other BRAF-mutant tumor types, this time evaluating dabrafenib combined with trametinib.