Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma

Abstract

Purpose 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 radiation (RT) in human HGGs in vitro and in vivo. Methods 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. Results 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. Conclusions 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.

Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies

“…This finding may have been partially influenced by the slightly lower frequency of EGFRvIII expression of 20.1% (36/179) in our dataset relative to the reported 30% incidence. 20,21 The BRAF mutation is present in only a small proportion of high-grade gliomas, 22 and we found this mutation in only 3.1% of GBM. Of these 7 tumors, only 1 was positive for both PD-1 and PD-L1 (Fig.…”

Clinicopathological and genetic association between epithelioid glioblastoma and pleomorphic xanthoastrocytoma

“…There have been some reports that patients with BRAF‐mutant PXA showed good prognosis, while other low‐grade gliomas (GG, PA, pilomyxoid astrocytoma and diffuse astrocytoma) with BRAF‐mutation contributed to poor prognosis . Several PXA cases with BRAF mutation demonstrated remarkable tumor regression by the treatment with BRAF inhibitor . Based on the impact of BRAF mutation on prognosis and therapeutic response, mutant BRAF‐targeted therapies with vemurafenib (NCT01748149) or darafinib (NCT02684058) against pediatric brain tumor with BRAF V600E mutation are currently under clinical trials (https://www.clinicaltrials.gov).…”

Spinal cord anaplastic astrocytoma with BRAF V600E mutation: A case report and review of literature

“…Recently, molecular therapy targeting the BRAF V600E mutation has been applied in clinical practice for malignant melanomas and other types of malignant tumors . For intracranial HGGs, the efficacy of BRAF inhibitors has been reported in laboratory and clinical studies . Although genetic analysis has been performed in several cases of spinal cord HGGs, most reports did not describe the BRAF V600E .…”