Efficacy and Safety of Trametinib in Neurofibromatosis Type 1-Associated Plexiform Neurofibroma and Low-Grade Glioma: A Systematic Review and Meta-Analysis

Wang, Dun; Ge, Lingling; Guo, Zizhen; Li, Yuehua; Zhu, Beiyao; Wang, Wei; Wei, Cheng-Jiang; Li, Qingfeng; Wang, Zhichao

doi:10.3390/ph15080956

Cited by 15 publications

(14 citation statements)

References 65 publications

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“…Wladis et al previously implicated p38 and ERK in the pathogenesis of rosacea, 9 suggesting a role for suppression of the MAPK pathway to arrest rosacea. MAPK inhibition has emerged as a meaningful treatment strategy for several diseases, including melanoma, non‐small cell lung cancer, and neurofibromatosis 33–35 . The current study repurposed an FDA‐approved MEK inhibitor as a topical preparation to target rosacea.…”

Section: Discussionmentioning

confidence: 99%

Safety and tolerability of topical trametinib in rosacea: Results from a phase I clinical trial

Wladis,

Busingye,

Saavedra

et al. 2024

Skin Health and Disease

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PurposeOveractivation of the mitogen activated kinase pathway has been associated with rosacea. We hypothesised that inhibitors of this pathway can be repurposed to alleviate rosacea symptoms.MethodsIn order to test this hypothesis, we designed a double‐blind, randomised, placebo‐controlled phase I clinical trial to assess the safety and tolerability of a first‐in‐kind topical formulation of a MEK kinase inhibitor, trametinib. Subjects applied daily trametinib‐containing cream (0.05 mg in 0.5 mL) to one cheek and cream without inhibitor to the other for consecutive 21 days. Skin irritation scores and blood samples were obtained during visits on days 8, 15 and 22.ResultsOn analysis of high‐performance liquid chromatography, no systemic trametinib absorption was detected during this treatment period. Subjects demonstrated a slight but significant improvement in both cheeks, regardless of drug contents. No adverse effects were reported during this time.ConclusionsTopical trametinib was well tolerated at a dose of 0.05 mg per day without meaningful systemic absorption or local adverse events. A dose escalation trial is warranted to determine optimal dosing to treat rosacea while avoiding the adverse effects of systemic treatment.

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Section: Discussionmentioning

confidence: 99%

Safety and tolerability of topical trametinib in rosacea: Results from a phase I clinical trial

Wladis,

Busingye,

Saavedra

et al. 2024

Skin Health and Disease

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“…Selumetinib was the first drug studied in the treatment of NF1‐LGGs, for which it has proven to be effective 11 . In terms of trametinib, a recent systematic review and meta‐analysis regarding the efficacy and safety of trametinib in NF1‐associated PN and LGG has been published 20 that included eight studies and involved 92 patients. Their results indicate a satisfactory ability to stabilize tumor progression (the disease control rate was 99.8%) but a more limited ability to shrink tumors (the objective response rate was 45.3%) with trametinib in NF1‐related nerve tumors.…”

Section: Discussionmentioning

confidence: 99%

Antiseizure effect of MEK inhibitor in a child with neurofibromatosis type 1—Developmental and epileptic encephalopathy and optic pathway glioma

Barrière,

Faure‐Conter,

Leblond

et al. 2023

Epileptic Disorders

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BackgroundNeurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder due to a mutation in NF1 gene, resulting in phenotypically heterogeneous systemic manifestations. Patients with NF1 are prone to develop neoplasms of the central nervous system (CNS) and are particularly at risk for optic pathway gliomas (OPG). Epilepsy is another recognized neurologic complication in patients with NF1, with a prevalence estimated between 4% and 14%. Several case reports and early phase clinical trials have demonstrated that the mitogen‐activated protein kinase inhibitors (MEKi) are effective in NF1‐low‐grade gliomas (LGGs), but their influence on seizure activity in humans has not been established.Case studyHere, we report a patient with NF1 and developmental and epileptic encephalopathy (DEE) harboring pharmacoresistant tonic seizures, and progressive optic pathway glioma (OPG). By using a MEKi therapy for her OPG, we observed an end to epileptic seizures as well as a significant improvement of interictal EEG abnormalities, despite a lack of tumor reduction.ConclusionMEK inhibitor therapy should be considered for patients with NF1 and refractory epilepsy.

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“…The proposed deep learning model, Multi-PEN, was used to estimate prognosis and search for prognostic genes in LGG patients. Other studies have utilized conventional and straightforward deep learning models, such as MLP, without considering current developments in deep learning [ 21 , 22 ]. Conversely, to find the prognostic genes, including miRNA, Multi-PEN exploits recent developments, i.e., residual networks and gene attention mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, grade II LGG tumors do involve the aforementioned histologic features [ 19 ]. Symptoms of LGG include headaches, vomiting, blurry vision, memory loss, nausea, and weakness on one side of the body [ 20 , 21 , 22 , 23 ]. LGG causes seizures more frequently than other brain cancers because it is produced in the cerebral cortex.…”

Section: Introductionmentioning

confidence: 99%

Estimating the Prognosis of Low-Grade Glioma with Gene Attention Using Multi-Omics and Multi-Modal Schemes

Choi

Lee

2022

Biology

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The prognosis estimation of low-grade glioma (LGG) patients with deep learning models using gene expression data has been extensively studied in recent years. However, the deep learning models used in these studies do not utilize the latest deep learning techniques, such as residual learning and ensemble learning. To address this limitation, in this study, a deep learning model using multi-omics and multi-modal schemes, namely the Multi-Prognosis Estimation Network (Multi-PEN), is proposed. When using Multi-PEN, gene attention layers are employed for each datatype, including mRNA and miRNA, thereby allowing us to identify prognostic genes. Additionally, recent developments in deep learning, such as residual learning and layer normalization, are utilized. As a result, Multi-PEN demonstrates competitive performance compared to conventional models for prognosis estimation. Furthermore, the most significant prognostic mRNA and miRNA were identified using the attention layers in Multi-PEN. For instance, MYBL1 was identified as the most significant prognostic mRNA. Such a result accords with the findings in existing studies that have demonstrated that MYBL1 regulates cell survival, proliferation, and differentiation. Additionally, hsa-mir-421 was identified as the most significant prognostic miRNA, and it has been extensively reported that hsa-mir-421 is highly associated with various cancers. These results indicate that the estimations of Multi-PEN are valid and reliable and showcase Multi-PEN’s capacity to present hypotheses regarding prognostic mRNAs and miRNAs.

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Efficacy and Safety of Trametinib in Neurofibromatosis Type 1-Associated Plexiform Neurofibroma and Low-Grade Glioma: A Systematic Review and Meta-Analysis

Cited by 15 publications

References 65 publications

Safety and tolerability of topical trametinib in rosacea: Results from a phase I clinical trial

Safety and tolerability of topical trametinib in rosacea: Results from a phase I clinical trial

Antiseizure effect of MEK inhibitor in a child with neurofibromatosis type 1—Developmental and epileptic encephalopathy and optic pathway glioma

Estimating the Prognosis of Low-Grade Glioma with Gene Attention Using Multi-Omics and Multi-Modal Schemes

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