ArticleNeuro-oncology2023
The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models.
Article in Neuro-oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 46 citations in OpenAlex.
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- Combinatorial Targeting of Avapritinib-Driven MAP Kinase Activation in High-Grade Glioma.Research square · 2026Article
- Targeted Therapy and Immunotherapies in Hepatocellular Carcinoma: Mechanisms and Clinical Studies.MedComm · 2026Review
- RAS/MAPK inhibition in pediatric gliomas.Neuro-oncology advances · 2026Review
- The future of targeted therapies for pediatric central nervous system tumors.Neuro-oncology advances · 2026Review
- MEK inhibition in adult patients with pilocytic astrocytomas.NPJ precision oncology · 2026Article
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- Targeting the MAPK Pathway in Cancer.International journal of molecular sciences · 2025Review
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- DUSP8 as a regulator of glioblastoma stem-like cell contribution to tumor vascularization.Journal of experimental & clinical cancer research : CR · 2025Article
- Multi-omics dissection of MAPK-driven senescence unveils therapeutic vulnerabilities in KIAA1549::BRAF-fusion pediatric low-grade glioma models.Signal transduction and targeted therapy · 2025Article
- RAS Pathway Mutations and Therapeutics in Vascular Anomalies.Pediatric blood & cancer · 2025Review
- Experimental Insights and Recommendations for Successfully Performing Cerebral Microdialysis With Hydrophobic Drug Candidates.Clinical and translational science · 2025Review
- Development of Novel PANoptosis-Related Gene Signatures to Predict the Prognosis of Patients With Stomach Adenocarcinoma.Human mutation · 2025Article
- Single-cell multi-omics sequencing uncovers region-specific plasticity of glioblastoma for complementary therapeutic targeting.Science advances · 2024Article
- A clinically compatible in vitro drug-screening platform identifies therapeutic vulnerabilities in primary cultures of brain metastases.Journal of neuro-oncology · 2024Article
- Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma.The Journal of clinical investigation · 2024Article
- Molecular Determinants for Photodynamic Therapy Resistance and Improved Photosensitizer Delivery in Glioma.International journal of molecular sciences · 2024Review
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29 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundPediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors.
methodsWe investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAFV600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing.
resultsUlixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of antiproliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival.
conclusionsThese data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.
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