Document Type
Article
Publication Date
3-1-2026
Original Citation
Johnson K,
Tien A,
Jiang J,
McNamara J,
Chang Y,
Montgomery C,
DeSantis A,
Elena-Sanchez L,
Fujita Y,
Kim S,
Spitzer A,
Gabriel P,
Flynn W,
Courtois E,
Hong A,
Harmon J,
Umemura Y,
Tovmasyan A,
Li J,
Mehta S,
Verhaak R,
Sanai N.
Single-nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a Phase 0/1 trial of recurrent high-grade glioma. Neuro Oncol. 2026;28(3):659–71.
Keywords
JGM, SS1, Humans, Glioma, Aminopyridines, Cyclin-Dependent Kinase 4, Female, Purines, Cyclin-Dependent Kinase 6, Brain Neoplasms, Male, Middle Aged, Neoplasm Recurrence, Local, Adult, Transcriptome, Everolimus, MTOR Inhibitors, TOR Serine-Threonine Kinases, Aged, Antineoplastic Combined Chemotherapy Protocols, Neoplasm Grading, Prognosis, Biomarkers, Tumor, Follow-Up Studies
JAX Source
Neuro Oncol. 2026;28(3):659–71.
ISSN
1523-5866
PMID
41206763
DOI
https://doi.org/10.1093/neuonc/noaf257
Abstract
BACKGROUND: Outcomes 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.
METHODS: A 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.
RESULTS: Median 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.
CONCLUSIONS: This 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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