Targeted therapy for BRAF V600E malignant astrocytoma

Theodore P. Nicolaides*, Huifang Li, David A. Solomon, Sujatmi Hariono, Rintaro Hashizume, Krister Barkovich, Suzanne J. Baker, Barbara S. Paugh, Chris Jones, Tim Forshew, Guy F. Hindley, J. Graeme Hodgson, Jung Sik Kim, David H. Rowitch, William A. Weiss, Todd A. Waldman, C. David James

*Corresponding author for this work

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)7595-7604
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number24
DOIs
Publication statusPublished - Dec 15 2011

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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