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Single-nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a Phase 0/1 trial of recurrent high-grade glioma.

Overview

Authors: Kevin C Johnson1, An-Chi Tien2, Jun Jiang3, James McNamara2, Yu-Wei Chang2, Chelsea Montgomery2, Anita DeSantis2, Leonel Elena-Sanchez2, Yoko Fujita2, Seongho Kim3, Avishay Spitzer4,5,6, Paul Gabriel7, William F Flynn7, Elise T Courtois7,8, Amy Hong2, Jocelyn Harmon2, Yoshie Umemura2, Artak Tovmasyan2, Jing Li2,3, Shwetal Mehta2, Roel G W Verhaak1, Nader Sanai2
ORCID iDs: Roel G W Verhaak
  1. Department of Neurosurgery, Yale School of Medicine, New Haven
  2. Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix
  3. Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit (J.J., S.K., J.L.)
  4. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot
  5. Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv
  6. Faculty of Medicine, Tel Aviv University, Tel Aviv
  7. The Jackson Laboratory for Genomic Medicine, Farmington
  8. Department of Obstetrics and Gynecology, UConn Health, Farmington
Institutions: Yale University (United States); Barrow Neurological Institute (United States); Wayne State University (United States); The Barbara Ann Karmanos Cancer Institute (United States); Tel Aviv University (Israel); Tel Aviv Sourasky Medical Center (Israel); Weizmann Institute of Science (Israel); The Jackson Laboratory for Genomic Medicine (United States); UConn Health (United States)
Journal: Neuro-oncology, volume 28, issue 3, pages 659-671
Dates: received 26 March 2025; accepted 3 November 2025; published online 8 November 2025; in print March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1093/neuonc/noaf257 · PMID 41206763 · PMCID PMC13070491 · OpenAlex W4416098848
Open access: hybrid, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), other condition (population), clinical / translational (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions
Keywords: CDK4, glioblastoma, glioma, plasticity, ribociclib, single cell, targeted therapy
MeSH: Antineoplastic Combined Chemotherapy Protocols*, Brain Neoplasms*, Cyclin-Dependent Kinase 4*, Cyclin-Dependent Kinase 6*, Glioma*, MTOR Inhibitors*, Neoplasm Recurrence, Local*, Transcriptome*, Adult, Aged, Aminopyridines, Biomarkers, Tumor, Everolimus, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Grading, Prognosis, Purines, TOR Serine-Threonine Kinases (* major topic)
Topic: Glioma Diagnosis and Treatment (Genetics, Medicine), according to OpenAlex
Funding: NIH HHS (R01 CA230725, R01 CA264934, R01 CA244170, R01 CA255124, R01 NS123038, R01 CA271431, R01 CA271601, R01 CA237208, R01 CA260003-01A1); National Institutes of Health (R01 CA244170, R01 CA255124, R01 CA271431, R01 NS123038, R01 CA264934, R01 CA271601, R01 CA230725, R01 CA237208, R01 CA260003-01A1); Barrow Neurological Foundation; Ben and Catherine Ivy Foundation
Citations: cited by 7 papers (Europe PMC); 28 references in the paper

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. Clini­calTrials.gov identifier: NCT03834740.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

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Data

Datasets cited

Data Availability

All analyses were performed in R 4.2.0. Gene expression count matrices processed by cellranger have been deposited to ­Synapse (https://www.synapse.org/Synapse:syn60087246/wiki/628483).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 22 authors, 7 keywords, 22 MeSH terms, 4 funders, 28 references.

Cite

This paper

Johnson, K. C., Tien, A.-C., Jiang, J., McNamara, J., Chang, Y.-W., Montgomery, C., DeSantis, A., Elena-Sanchez, L., Fujita, Y., Kim, S., Spitzer, A., Gabriel, P., Flynn, W. F., Courtois, E. T., Hong, A., Harmon, J., Umemura, Y., Tovmasyan, A., Li, J., . . . Sanai, N. (2026). Single-nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a Phase 0/1 trial of recurrent high-grade glioma. Neuro-oncology, 28(3), 659-671. https://doi.org/10.1093/neuonc/noaf257

BibTeX

@article{johnson2026single,
author = {Johnson, Kevin C and Tien, An-Chi and Jiang, Jun and McNamara, James and Chang, Yu-Wei and Montgomery, Chelsea and DeSantis, Anita and Elena-Sanchez, Leonel and Fujita, Yoko and Kim, Seongho and Spitzer, Avishay and Gabriel, Paul and Flynn, William F and Courtois, Elise T and Hong, Amy and Harmon, Jocelyn and Umemura, Yoshie and Tovmasyan, Artak and Li, Jing and Mehta, Shwetal and Verhaak, Roel G W and Sanai, Nader},
title = {{Single-nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a Phase 0/1 trial of recurrent high-grade glioma}},
journal = {Neuro-oncology},
year = {2026},
month = mar,
volume = {28},
number = {3},
pages = {659--671},
publisher = {Oxford University Press},
issn = {1522-8517},
doi = {10.1093/neuonc/noaf257},
url = {https://doi.org/10.1093/neuonc/noaf257},
pmid = {41206763},
pmcid = {PMC13070491}
}

RIS

TY - JOUR
AU - Johnson, Kevin C
AU - Tien, An-Chi
AU - Jiang, Jun
AU - McNamara, James
AU - Chang, Yu-Wei
AU - Montgomery, Chelsea
AU - DeSantis, Anita
AU - Elena-Sanchez, Leonel
AU - Fujita, Yoko
AU - Kim, Seongho
AU - Spitzer, Avishay
AU - Gabriel, Paul
AU - Flynn, William F
AU - Courtois, Elise T
AU - Hong, Amy
AU - Harmon, Jocelyn
AU - Umemura, Yoshie
AU - Tovmasyan, Artak
AU - Li, Jing
AU - Mehta, Shwetal
AU - Verhaak, Roel G W
AU - Sanai, Nader
TI - Single-nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4/6 and mTOR inhibition in a Phase 0/1 trial of recurrent high-grade glioma
T2 - Neuro-oncology
J2 - Neuro Oncol
PY - 2026
DA - 2026/03/01
VL - 28
IS - 3
SP - 659
EP - 671
SN - 1522-8517
PB - Oxford University Press
DO - 10.1093/neuonc/noaf257
UR - https://doi.org/10.1093/neuonc/noaf257
LA - en
ER -

CSL-JSON

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