# Project 3 - Targeting CDK4/6 to modulate immunogenicity in gliomas (Wen/Zhao)

> **NIH NIH P50** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $353,666

## Abstract

Glioblastoma (GBM), the most common primary malignant brain tumor of adults, is a significant cause of
patient morbidity and mortality for which effective treatments are lacking. The cyclin D1-cyclin dependent
kinase 4/6-retinoblastoma (cyclinD1-CDK4/6-Rb) signaling axis is genetically activated in majority of GBM
(~80%) via genomic loss of CDKN2A/B, amplification of CDK4/6 or deletion/mutation of RB1. CDK4/6 has
been targeted based on the notion that suppressing the phosphorylation of pRB by CDK4/6 will lead to cell
cycle arrest. Beyond suppressing cell cycle progression, we recently found that CDK4/6 antagonists promote
anti-tumor immunity. The molecular mechanisms underlying this are exerted at two levels: (i) a tumor cellautonomous
enhancement of the antigen processing and presentation machinery and (ii) a non-tumor cellautonomous,
systemic decrease of the Treg/CD8+ ratio. Collectively, these effects promote cytotoxic T cellmediated
clearance of tumor cells, which is further enhanced by the addition of immune checkpoint blockade
therapeutics. Notably the actions of the combination of CDK4/6 inhibition and checkpoint blockade was much
greater than additive in our preclinical models. CDK4/6 inhibitors are FDA-approved for the treatment of
estrogen receptor (ER)-positive metastatic breast cancer, where they now present a well-tolerated, first-line
therapy that improves progression-free survival. Their efficacy against GBM is unknown. However, early
unpublished clinical data suggest that, like most targeted therapies, CDK4/6 inhibitors as single agents may
have only modest benefit. Similarly, early data on immune checkpoint blockade have not been promising in
recurrent GBM in which recently this class of drug failed to improve survival as single agent therapy. Building
upon our recent findings, we hypothesize that brain penetrant CDK4/6 inhibitors could augment
immunotherapy approaches for GBM including PD-1 checkpoint inhibitors for recurrent GBM. This proposal
has three specific aims designed to investigate the therapeutic approach of combined CDK4/6 inhibition and
immune checkpoint blockade (ICB) in GBM in both preclinical and clinical settings: (Aim 1) To assess the
effects of CDK4/6 inhibition on GBM cell-intrinsic immune response; (Aim 2) To assess the effects of CDK4/6
inhibition on enhancing immunotherapy in syngeneic models of GBM; and (Aim 3) To evaluate the impact of
CDK4/6 inhibitors on immune function and clinical outcome for GBM patients. By using patient-derived GBM
tumors and syngeneic mouse models of GBM, we will determine the preclinical efficacy of CDK4/6 inhibitors in
combination with immunotherapy against GBM, further solidifying the preclinical rationale to design clinical
trials for patients with GBM.

## Key facts

- **NIH application ID:** 10245087
- **Project number:** 5P50CA165962-08
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Jean Zhao
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $353,666
- **Award type:** 5
- **Project period:** 2013-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245087

## Citation

> US National Institutes of Health, RePORTER application 10245087, Project 3 - Targeting CDK4/6 to modulate immunogenicity in gliomas (Wen/Zhao) (5P50CA165962-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245087. Licensed CC0.

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