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Published on: October 27, 2014
Targeted therapy for BRAFV600E malignant astrocytoma
Theodore P Nicolaides1, Huifang Li, David A Solomon
1University of California, San Francisco, San Francisco, CA 94158, USA.
Summary
Activating BRAF(V600E) mutations occur in 10% of pediatric malignant astrocytomas (MA). BRAF(V600E)-specific inhibitors show promise for treating these aggressive brain tumors.
Area of Science:
- Neuro-oncology
- Molecular biology
- Cancer genetics
Background:
- Malignant astrocytomas (MA) are aggressive pediatric brain tumors with poor prognoses.
- Activating BRAF(V600E) mutations are found in a subset of MAs, particularly in children.
Purpose of the Study:
- To determine the incidence of BRAF(V600E) in pediatric MA patient cohorts.
- To evaluate the therapeutic effects of BRAF blockade in preclinical MA models with BRAF(V600E) and wild-type BRAF.
Main Methods:
- BRAF(V600E) mutation analysis in two pediatric MA cohorts.
- In vitro studies using MA cell lines to assess BRAF shRNA knockdown and pharmacologic inhibition (PLX4720).
- In vivo efficacy studies using orthotopic MA xenografts in mice.
Main Results:
- BRAF(V600E) mutations were identified in 10-11% of pediatric MAs.
- BRAF(V600E)-specific inhibitor PLX4720 demonstrated antiproliferative effects on mutant cells in vitro.
- PLX4720 reduced tumor growth and improved survival in mice with BRAF(V600E) MA xenografts, but was ineffective or tumor-promoting in wild-type xenografts.
Conclusions:
- Approximately 10% of pediatric malignant astrocytomas harbor activating BRAF(V600E) mutations.
- BRAF(V600E)-specific inhibitors warrant clinical evaluation for treating pediatric MA patients with this mutation.
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