ArticleNeuro-oncology2026
Single-nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a Phase 0/1 trial of recurrent high-grade glioma.
Article in Neuro-oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03834740 (A Phase 0/I Study of Ribociclib), which is not on this map. Cited by 8 papers.
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The trial behind it
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.
A Phase 0/I Study of Ribociclib (LEE011) in Combination With Everolimus in Preoperative Rb-Intact Recurrent High-Grade Glioma Patients Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration
Who cites it
8 citing papers in PubMed.
- Article
- Article
- Critical role of cell competition in gliomagenesis.bioRxiv : the preprint server for biology · 2026Article
- Optimizing ribociclib dosing in breast cancer with brain metastasis patients using a physiologically based pharmacokinetic model.BMC cancer · 2026Article
- SpatialCNS-PBPK: An R/Shiny Web-Based Application for Physiologically Based Pharmacokinetic Modeling of Spatial Pharmacokinetics in the Human Central Nervous System and Brain Tumors.CPT: pharmacometrics & systems pharmacology · 2025Article
- Mechanistic Modeling of Spatial Heterogeneity of Drug Penetration and Exposure in the Human Central Nervous System and Brain Tumors.Clinical pharmacology and therapeutics · 2025Article
- Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer.Nature cancer · 2025Review
- A phase 0 clinical trial to evaluate the neuropharmacological profile of posaconazole for glioblastoma.Neuro-oncology advancesArticle
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22 authors.
Funding
Abstract
backgroundOutcomes for adult patients with high-grade glioma (HGG) remain poor, necessitating new treatment strategies. Key challenges include poor drug penetration in the brain and malignant cell state plasticity. Phase 0 studies identify agents that achieve target modulation through pharmacologically relevant brain concentrations.
methodsA Phase 0/1 clinical trial combined the 2 targeted inhibitors ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) in recurrent HGG patients, aiming to identify brain-penetrant combinations and assess their impact on malignant cell states. We enrolled 24 patients with recurrent HGG, characterized by CDKN2A/B deletion or CDK4/6 amplification, PTEN loss or PIK3CA mutations, and wildtype retinoblastoma protein (Rb). Tumors were evaluated for pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics.
resultsMedian unbound ribociclib concentrations in gadolinium non-enhancing tumor regions were significantly above the biochemical IC50 for CDK4/6 inhibition at 400 and 600 mg QD doses. Unbound everolimus concentrations were undetectable (<0.1 nM) in tumor regions across all dose levels. Ribociclib treatment was associated with significantly decreased Ki-67-positive cells. Single-nucleus RNA sequencing of 17 on-trial IDH-wildtype recurrences and 88 standard-of-care-treated recurrences showed a significantly lower fraction of cycling and neural progenitor-like malignant cell populations in ribociclib-everolimus-treated tumors. CDK4/6 inhibitor-directed malignant cell state shifts were validated using 3 patient-derived cell lines.
conclusionsThis trial underscores the value of integrating pharmacokinetics, pharmacodynamics, and single-nucleus transcriptomics in Phase 0/1 surgical studies to assess treatment effects, including malignant cell state shifts. Clini-calTrials.gov identifier: NCT03834740.
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