ArticlePediatric blood & cancer2010
Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program.
Article in Pediatric blood & cancer, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
64 citing papers in PubMed.
- Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.The Lancet. Oncology · 2019Trial
- A phase II study of eribulin in recurrent or refractory osteosarcoma: A report from the Children's Oncology Group.Pediatric blood & cancer · 2019Trial
- Population Pharmacokinetics of Selumetinib and Its Metabolite N-desmethyl-selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low-Grade Gliomas.CPT: pharmacometrics & systems pharmacology · 2017Trial
- Article
- Dual inhibition of MAPK and TORC1 signaling retards development of radiation resistance in pediatric BRAFV600E glioma models.Neuro-oncology · 2025Article
- Lessons learned from 20 years of preclinical testing in pediatric cancers.Pharmacology & therapeutics · 2024Review
- Integrated analyses reveal two molecularly and clinically distinct subtypes of H3 K27M-mutant diffuse midline gliomas with prognostic significance.Acta neuropathologica · 2024Article
- Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines.Journal of neuro-oncology · 2024Article
- Advances in the treatment of BRAF-mutant low-grade glioma with MAPK inhibitors.Translational pediatrics · 2024Article
- Generation of patient-derived pediatric pilocytic astrocytoma in-vitro models using SV40 large T: evaluation of a modeling workflow.Journal of neuro-oncology · 2023Article
- Optimizing preclinical pediatric low-grade glioma models for meaningful clinical translation.Neuro-oncology · 2023Article
- Redundant Signaling as the Predominant Mechanism for Resistance to Antibodies Targeting the Type-I Insulin-Like Growth Factor Receptor in Cells Derived from Childhood Sarcoma.Molecular cancer therapeutics · 2023Article
- The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models.Neuro-oncology · 2023Article
- Pediatric low-grade glioma models: advances and ongoing challenges.Frontiers in oncology · 2023Review
- Successes and challenges in modeling heterogeneous BRAFFrontiers in oncology · 2023Review
- MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus.Neuro-oncology · 2022Review
- Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- Imaging diagnosis and treatment selection for brain tumors in the era of molecular therapeutics.Cancer imaging : the official publication of the International Cancer Imaging Society · 2022Review
- Vertical Inhibition of the RAF-MEK-ERK Cascade Induces Myogenic Differentiation, Apoptosis, and Tumor Regression inMolecular cancer therapeutics · 2022Article
- Clinical Pharmacokinetics and Pharmacodynamics of Selumetinib.Clinical pharmacokinetics · 2021Review
4 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors.
Funding
Abstract
backgroundAZD6244 (ARRY-142886) is a potent small molecule inhibitor of MEK1/2 that is in phase 2 clinical development. PROCEDURES: AZD6244 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM-10 microM). In vivo AZD6244 was tested at a dose of 100 mg/kg administered orally twice daily 5 days per week for 6 weeks. Subsequently, AZD6244 was evaluated against two juvenile pilocytic astrocytoma (JPA) xenografts using once and twice daily dosing schedules. Phosphorylation of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was determined by immunoblotting.
resultsAt the highest concentration used in vitro (10 microM) AZD6244 only inhibited growth by 50% in 5 of the 23 cell lines. Against the in vivo tumor panels, AZD6244 induced significant differences in EFS distribution in 10 of 37 (27%) solid tumor models and 0 of 6 acute lymphoblastic leukemia (ALL) models. There were no objective responses. Pharmacodynamic studies indicated at this dose and schedule AZD6244 completely inhibited ERK1/2 phosphorylation. AZD6244 was evaluated against two JPA xenografts, BT-35 (wild-type BRAF) and BT-40 (mutant [V600E] BRAF). BT-40 xenografts were highly sensitive to AZD6244, whereas BT-35 xenografts progressed on AZD6244 treatment.
conclusionsAt the dose and schedule of administration used, AZD6244 as a single agent had limited in vitro and in vivo activity against the PPTP tumor panels despite inhibition of MEK1/2 activity. However, AZD6244 was highly active against BT-40 JPA xenografts that harbor constitutively activated BRAF, causing complete regressions.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.