Vemurafenib and cobimetinib overcome resistance to vemurafenib in
            <i>BRAF</i>
            -mutant ganglioglioma

Touat, Mehdi; Gratieux, Julie; Auliac, S.; Sejean, Karine; Aldéa, Sorin; Savatovsky, Julien; Perkins, Géraldine; Blons, Hélène; Ligon, Keith L.; Idbaïh, Ahmed; Hollebecque, Antoine; Gimenez-Roqueplo, Anne-Paule; Laurent‐Puig, Pierre; Sanson, Marc; Villa, Chiara; Stefano, Anna Luisa Di

doi:10.1212/wnl.0000000000006171

Cited by 20 publications

(13 citation statements)

References 8 publications

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“…Evidence from the phase 2 VE‐basket study supports the use of single‐agent BRAF inhibition in BRAF V600E mutant gliomas, which included three anaplastic gangliogliomas . Other case reports have reported the activity of the combination of BRAF and MEK inhibition in high‐grade gangliogliomas, and of single‐agent BRAF inhibition in low‐grade ganglioglioma . To our knowledge, there are no previously published reports of combined BRAF and MEK inhibition in low‐grade ganglioglioma.…”

Section: What Is Known and Objectivesmentioning

confidence: 89%

Combination of BRAF and MEK inhibition in BRAF V600E mutant low‐grade ganglioglioma

Yau

Ameratunga

2020

J Clin Pharm Ther

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What is known and objective Post‐surgical management of low grade gangliogliomas is controversial with paucity of data for the use of chemotherapy. BRAF mutations are present in a number of glioma subtypes and offer an opportunity for treatment with targeted therapy. Case summary A 32‐year‐old man with an unresectable, BRAF V600E mutant, WHO grade 1 ganglioglioma is commenced on combination BRAF and MEK inhibition (vemurafenib and cobimetinib). Partial radiological and clinical response was noted after 13 weeks of treatment. Treatment complication with grade 2 skin and liver toxicity was resolved with dose interruption and reduction. What is new and conclusion Combination BRAF and MEK inhibition present a safe and feasible treatment strategy in unresectable BRAF V600E mutant low grade ganglioglioma.

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Section: What Is Known and Objectivesmentioning

confidence: 89%

Combination of BRAF and MEK inhibition in BRAF V600E mutant low‐grade ganglioglioma

Yau

Ameratunga

2020

J Clin Pharm Ther

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“…The response to vemurafenib in our patient was consistent with the response to BRAF inhibitors observed in previously reported cases, including one case of spinal ganglioglioma in a 2-year-old child (29). However, all cases except for one were located in the cerebrum or were brainstem gangliogliomas, with half of the cases being anaplastic gangliogliomas (9/19) (28, 32–36). In eight cases (8/19) (26, 27, 32–34, 36, 37), the BRAF inhibitor was associated with another treatment or surgery, making the analysis of the response to the BRAF inhibitor difficult.…”

Section: Discussionmentioning

confidence: 99%

“…However, all cases except for one were located in the cerebrum or were brainstem gangliogliomas, with half of the cases being anaplastic gangliogliomas (9/19) (28, 32–36). In eight cases (8/19) (26, 27, 32–34, 36, 37), the BRAF inhibitor was associated with another treatment or surgery, making the analysis of the response to the BRAF inhibitor difficult. Based on the analysis of the present case and previously reported cases, a complete response was obtained in 15% (3/20) and partial response in 50% (10/20) of cases at a median of 3.2 months after starting treatment and the estimated progression-free survival was 14 months.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, BRAF/MEK double blockade with vemurafenib and cobimetinib or dabrafenib and trametinib was shown to be a more effective strategy than targeting BRAF alone in patients with BRAF -mutant advanced melanoma (72). Dual BRAF/MEK inhibition has also been suggested as a promising activity in BRAF-mutant gliomas that may overcome (36, 73) vemurafenib resistance. A prospective study is needed to assess the efficacy of this combination in gangliogliomas.…”

Section: Discussionmentioning

confidence: 99%

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Prolonged Response Induced by Single Agent Vemurafenib in a BRAF V600E Spinal Ganglioglioma: A Case Report and Review of the Literature

et al. 2019

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Spinal ganglioglioma is a rare low-grade, slow-growing tumor of the central nervous system affecting mostly children and young adults. After surgery, some patients show tumor recurrence and/or malignant transformation. Gangliogliomas harbor molecular deficiencies such as mutations in the B-rapidly accelerated fibrosarcoma ( BRAF ) gene, resulting in activation of a downstream signaling pathway and cancer development. Vemurafenib is a BRAF inhibitor used to treat patients with BRAF V600E -mutated cancer. Although a few studies have reported the clinical responses in gangliogliomas, the sequence and duration of treatment have not been established. We describe a case of an adult with a progressive BRAF V600E mutant spinal cord ganglioglioma 9 years after surgery who was treated with vemurafenib. This treatment resulted in a partial response within 2 months, which was sustained for more than a year. The patient then decided to stop treatment because of side effects. Despite this decision, the tumor showed no sign of progression 21 months after treatment discontinuation. This is the first reported case of a response to vemurafenib in an adult with progressive spinal cord BRAF V600E -mutated ganglioglioma which was sustained after treatment discontinuation.

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“…In another case report on anaplastic ganglioglioma, tumor resection was followed by vemurafenib administration; since BRAF inhibition induces a sustained activation of MAPK, which may contribute to drug resistance, Touat et al co-administered vemurafenib plus cobimetinib, a MEK inhibitor. The patients receiving the combination remained asymptomatic for 16 months, showed a good tolerance to the treatment, and did not show recurrence [392]. Vemurafenib induced a tumor size reduction in BRAFV600E-positive metastatic glioma [393].…”

Section: Vemurafenibmentioning

confidence: 91%

Autophagy as a Potential Therapy for Malignant Glioma

et al. 2020

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Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells.

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Vemurafenib and cobimetinib overcome resistance to vemurafenib in BRAF -mutant ganglioglioma

Cited by 20 publications

References 8 publications

Combination of BRAF and MEK inhibition in BRAF V600E mutant low‐grade ganglioglioma

Combination of BRAF and MEK inhibition in BRAF V600E mutant low‐grade ganglioglioma

Prolonged Response Induced by Single Agent Vemurafenib in a BRAF V600E Spinal Ganglioglioma: A Case Report and Review of the Literature

Autophagy as a Potential Therapy for Malignant Glioma

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