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- Title
Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma.
- Authors
Dasgupta, Tina; Olow, Aleksandra; Yang, Xiaodong; Hashizume, Rintaro; Nicolaides, Theodore; Tom, Maxwell; Aoki, Yasuyuki; Berger, Mitchel; Weiss, William; Stalpers, Lukas; Prados, Michael; David James, C.; Mueller, Sabine; Haas-Kogan, Daphne
- Abstract
Radiation (RT) is critical to the treatment of high-grade gliomas (HGGs) but cures remain elusive. The BRAF mutation V600E is critical to the pathogenesis of 10-20 % of pediatric gliomas, and a small proportion of adult HGGs. Here we aim to determine whether PLX4720, a specific BRAF V600E inhibitor, enhances the activity of RT in human HGGs in vitro and in vivo. Patient-derived HGG lines harboring wild-type BRAF or BRAF V600E were assessed in vitro to determine IC50 values, cell cycle arrest, apoptosis and senescence and elucidate mechanisms of combinatorial activity. A BRAF V600E HGG intracranial xenograft mouse model was used to evaluate in vivo combinatorial efficacy of PLX4720+RT. Tumors were harvested for immunohistochemistry to quantify cell cycle arrest and apoptosis. RT+PLX4720 exhibited greater anti-tumor effects than either monotherapy in BRAF V600E but not in BRAF WT lines. In vitro studies showed increased Annexin V and decreased S phase cells in BRAF V600E gliomas treated with PLX4720+RT, but no significant changes in β-galactosidase levels. In vivo, concurrent and sequential PLX4720+RT each significantly prolonged survival compared to monotherapies, in the BRAF V600E HGG model. Immunohistochemistry of in vivo tumors demonstrated that PLX4720+RT decreased Ki-67 and phospho-MAPK, and increased γH2AX and p21 compared to control mice. BRAF V600E inhibition enhances radiation-induced cytotoxicity in BRAF V600E-mutated HGGs, in vitro and in vivo, effects likely mediated by apoptosis and cell cycle, but not senescence. These studies provide the pre-clinical rationale for clinical trials of concurrent radiotherapy and BRAF V600E inhibitors.
- Subjects
GLIOMAS; BRAF genes; ENZYME inhibitors; GENETIC mutation; GLIOMA treatment; CHILDHOOD cancer; PATIENTS; CANCER treatment
- Publication
Journal of Neuro-Oncology, 2016, Vol 126, Issue 3, p385
- ISSN
0167-594X
- Publication type
Article
- DOI
10.1007/s11060-015-1939-2