Cancer Therapy: Preclinical Targeted Therapy for BRAF Malignant Astrocytoma

Purpose: Malignant astrocytomas (MA) are aggressive central nervous system tumors with poor prognosis. Activating mutation of BRAF (BRAF) has been reported in a subset of these tumors, especially in children. We have investigated the incidence of BRAF in additional pediatric patient cohorts and examined the effects of BRAF blockade in preclinical models of BRAF and wild-type BRAF MA. ExperimentalDesign:BRAFmutation statuswas examined in twopediatricMApatient cohorts. For functional studies,BRAFMAcell lineswere used to investigate the effects ofBRAF shRNAknockdown in vitro, and to investigate BRAF pharmacologic inhibition in vitro and in vivo. Results: BRAF 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 was identified in four instances. Using the BRAF-specific inhibitor PLX4720, pharmacologic blockade of BRAF revealed preferential antiproliferative activity against BRAFmutant cells in vitro, in contrast to the use of shRNA-mediated knockdown of BRAF, which inhibited cell growth of glioma cell lines regardless of BRAFmutation status. Using orthotopic MA xenografts, we show that PLX4720 treatment decreases tumor growth and increases overall survival inmice-bearing BRAFmutant xenografts, while being ineffective, and possibly tumor promoting, against xenografts with wild-type BRAF. Conclusions: Our results indicate a 10% incidence of activating BRAF among pediatric MAs. With regard to implications for therapy, our results support evaluation of BRAF-specific inhibitors for treating BRAF MA patients. Clin Cancer Res; 17(24); 7595–604. 2011 AACR.