Dabrafenib and trametinib in <i>BRAFV600E</i> mutated glioma

Brown, Nicholas F.; Carter, Thomas; Kitchen, Neil; Mulholland, Paul J.

doi:10.2217/cns-2017-0006

Cited by 52 publications

(33 citation statements)

References 29 publications

(32 reference statements)

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“…Moreover, we have shown that acquired dabrafenib resistance could be overcome by the MEK inhibitor trametinib. Our observations are consistent with the currently tested combination treatment of BRAF and MEK inhibitors in different BRAF V600E mutant gliomas types, including PXAs 60 .…”

Section: Discussionsupporting

confidence: 90%

Somatic genome editing with the RCAS-TVA-CRISPR-Cas9 system for precision tumor modeling

et al. 2018

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To accurately recapitulate the heterogeneity of human diseases, animal models require to recreate multiple complex genetic alterations. Here, we combine the RCAS-TVA system with the CRISPR-Cas9 genome editing tools for precise modeling of human tumors. We show that somatic deletion in neural stem cells of a variety of known tumor suppressor genes (Trp53, Cdkn2a, and Pten) leads to high-grade glioma formation. Moreover, by simultaneous delivery of pairs of guide RNAs we generate different gene fusions with oncogenic potential, either by chromosomal deletion (Bcan-Ntrk1) or by chromosomal translocation (Myb-Qk). Lastly, using homology-directed-repair, we also produce tumors carrying the homologous mutation to human BRAF V600E, frequently identified in a variety of tumors, including different types of gliomas. In summary, we have developed an extremely versatile mouse model for in vivo somatic genome editing, that will elicit the generation of more accurate cancer models particularly appropriate for pre-clinical testing.

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Section: Discussionsupporting

confidence: 90%

Somatic genome editing with the RCAS-TVA-CRISPR-Cas9 system for precision tumor modeling

et al. 2018

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“…And, more recently, there are reports of BRAF MEKi. Similarly, few case reports have shown promising results after combination therapy with BRAF MEKi in PXA patients with BRAF mutations [12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…The median progression-free survival was 5.5 months in all the gliomas treated, and more than 39.1 months in a PXA case [11]. There are several case reports of combined BRAF MEKi in PXA patients [12][13][14]. As well as an enhanced response to BRAF inhibition when combined with autophagy inhibition in glioma cell lines [15].…”

Section: Introductionmentioning

confidence: 99%

Using personalized medicine in gliomas: a genomic approach to diagnosis and overcoming treatment resistance in a case with pleomorphic xanthoastrocytoma

et al. 2019

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Introduction A patient who was initially considered to have a glioblastoma (GBM) had molecular analysis, showing that it was a pleomorphic xanthoastrocytoma (PXA). Up to 78% of PXA tumors have BRAF V600E mutations. Primary brain tumors with BRAF mutations can have a good response to BRAF MEK inhibitors (BRAF MEKi), and there may be a synergistic response when combined with autophagy inhibitors. Presentation of the case A 20-year-old man found to have a large brain mass with midline shift underwent resection. He was diagnosed with "GBM" and treated with radiation and temozolomide with subsequent disease recurrence. Review of histology showed malignant PXA with BRAF V600E mutation. Treatment with Dabrafenib and Trametinib was started, and tumor size increased in size after 14 months of treatment. Given studies showing that resistance to BRAF inhibition can be overcome by autophagy inhibition, chloroquine was added. Patient has been on "triple" therapy for 15 months and has radiographically Stable Disease. At MCC, 3% of patients with gliomas have BRAF mutations who could potentially benefit from this combination therapy. Conclusion This is the first report of a PXA patient receiving therapy with BRAF MEKi and an autophagy inhibitor with prolonged stable disease. This patient highlights the importance of a molecular interrogation in gliomas to provide an integrated diagnosis and effective treatment. This may be useful in up to 3% of glioma patients with BRAF mutations. Molecular testing in neuro-oncology is providing new avenues of diagnosis and treatment, and detailed molecular interrogation should be considered routine.

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“…They are more frequently encountered in younger patients, show early recurrence, and demonstrate rapid progression and leptomeningeal infiltration [ 3 , 5 ]. As targeted inhibitory antibody therapy has recently gained increasing attention in oncology, point mutation of the BRAF gene at codon 600 (BRAF V600E) may present as a target for potential treatment [ 2 , 7 ]. Interestingly, approximately half of epithelioid glioblastomas harbour the BRAF V600E mutation, thus exhibiting morphologic and molecular overlap with pleomorphic xanthoastrocytoma [ 1 – 5 ].…”

Section: Discussionmentioning

confidence: 99%

Imaging and Histopathologic Nuances of Epithelioid Glioblastoma

2018

Case Reports in Surgery

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A 27-year-old male without significant past medical history presented following collapse resulting from a syncopal episode at work. There was an episode of vomiting, and one of tonic-clonic seizure activity, which was spontaneously resolved after approximately one minute. His neurologic exam was nonfocal, with full strength in the bilateral upper and lower extremities, and no sensory deficits were elicited. MRI studies demonstrated a 4.7 cm rim-enhancing cystic mass in the right temporal-parietal region, with resultant mass effect and edema. At surgery, intraoperative pathologic consultation favoured a primary glial neoplasm. Subsequent complete histologic examination on permanent sections confirmed the presence of glioblastoma, with a morphologic pattern and immunohistochemical profile most consistent with epithelioid glioblastoma (WHO grade IV). Epithelioid glioblastoma is a rare, especially aggressive variant of IDH-wildtype glioblastoma, recognized in the 2016 World Health Organization classification. Approximately 50% of such tumors harbour the BRAF V600E mutation, which has also been observed in some melanomas where selective inhibitors have demonstrated a therapeutic role. The especially aggressive behaviour and poor clinical outcome typically observed for this variant of glioblastoma demonstrate the importance of emerging areas relevant to neurooncology, specifically those of proteomic characterization and therapeutic nanomedicine.

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Dabrafenib and trametinib in BRAFV600E mutated glioma

Cited by 52 publications

References 29 publications

Somatic genome editing with the RCAS-TVA-CRISPR-Cas9 system for precision tumor modeling

Somatic genome editing with the RCAS-TVA-CRISPR-Cas9 system for precision tumor modeling

Using personalized medicine in gliomas: a genomic approach to diagnosis and overcoming treatment resistance in a case with pleomorphic xanthoastrocytoma

Imaging and Histopathologic Nuances of Epithelioid Glioblastoma

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