Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma
Document Type
Article
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 two 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 three 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. ClinicalTrials.gov identifier: NCT03834740.
Keywords
CDK4, glioma, ribociclib, single cell, targeted therapy
Publication Date
11-8-2025
Publication Title
Neuro-oncology
E-ISSN
1523-5866
PubMed ID
41206763
Digital Object Identifier (DOI)
10.1093/neuonc/noaf257
Recommended Citation
Johnson, Kevin C.; Tien, An-Chi; Jiang, Jun; McNamara, James; Chang, Yu-Wei; Montgomery, Chelsea; DeSantis, Anita; Elena-Sanchez, Leonel; Fujita, Yoko; Kim, Seongho; Spitzer, Avishay; Gabriel, Paul; Flynn, William F.; Courtois, Elise T.; Hong, Amy; Harmon, Jocelyn; Umemura, Yoshie; Tovmasyan, Artak; Li, Jing; Mehta, Shwetal; Verhaak, Roel G.; and Sanai, Nader, "Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma" (2025). Translational Neuroscience. 2483.
https://scholar.barrowneuro.org/neurobiology/2483