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Ref Type

Journal Article

PMID

(39107839)

Authors

Steininger J, Buszello C, Oertel R, Meinhardt M, Schmid S, Engellandt K, Herold S, Stasik S, Ebrahimi A, Renner B, Thiede C, Eyüpoglu IY, Schackert G, Beissert S, Meier F, Radke J, Westphal D, Juratli TA

Title

Efficacy of BRAF/MEK-inhibitor therapy for epithelioid glioblastoma with a novel BRAFV600 mutation.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Acta neuropathologica communications	12	1	2024 Aug 06	124	Acta Neuropathol Commun

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Abstract Text

Epithelioid glioblastoma (eGB), a very aggressive and rare brain tumour, is associated with a dismal median overall survival. Effective therapies for patients with eGB, particularly with leptomeningeal dissemination, are still lacking. Here, we describe a case of a 25-year-old male diagnosed with an intramedullary cervical tumour with subsequent leptomeningeal disease. Histopathology identified a highly necrotising, epithelioid-type tumour with high cell density, most compatible with the diagnosis of an eGB. DNA analysis revealed an unprecedented B-Raf protooncogene, serine/threonine kinase (BRAF) gene variant in exon 15 (ENST00000288602.6, c.1799_1810delinsATG, p.(V600_W604delinsDG)), triggering activation of the mitogen-activated protein kinase (MAPK) pathway. Consequently, we initiated MAPK inhibitor (MAPKi) therapy, utilizing a combination of BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. Liquid chromatography-tandem mass spectrometry analysis confirmed the drugs' presence in the patient's cerebrospinal fluid, indicating their capacity to cross the blood-brain barrier. Remarkably, the patient responded very well to therapy and transitioned from a near-comatose state to significantly improved health, sustained for over three months. This study highlights that MAPKi, particularly targeted towards novel BRAFV600 mutations, might offer promising advancements in eGB treatment strategies.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	V600_W604delinsDG	indel	unknown	BRAF V600_W604delinsDG results in the deletion of five amino acids in the protein kinase domain of the Braf protein from amino acids 488 to 493, combined with the insertion of an aspartic acid (D) and a glycine (G) at the same site (UniProt.org). V600_W604delinsDG results in increased pERK expression in patient samples (PMID: 39107839), but has not been fully biochemically characterized and therefore, its effect on Braf protein function is unknown.

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600_W604delinsDG	glioblastoma	predicted - sensitive	Dabrafenib + Trametinib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with epithelioid glioblastoma harboring BRAF V600_W604delinsDG responded to treatment with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) with clinical improvement lasting 3 months (PMID: 39107839).	39107839

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