# Improving CDK 4/6 inhibition in the treatment of medulloblastoma

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $37,027

## Abstract

PROPOSAL ABSTRACT
 This proposal will develop CDK4/6 inhibitor therapy for medulloblastoma, using a novel, nanoparticle
formulation of palbociclib, studied in vivo in transgenic medulloblastoma-prone mice and combining with the
OLIG2 inhibitor CT-179. Medulloblastoma is the most common malignant pediatric brain tumor. New
medulloblastoma treatments are needed because current therapy with surgery radiation and chemotherapy fails
20% of patients and leaves survivors at risk for neurocognitive injury, growth defects, and psychosocial
impairment. While medulloblastoma is a heterogenous disease with four subgroups, all subgroups have intact
RB and require CDK4/6 activity. The CyclinD1/CDK4/6/Retinoblastoma pathway is therefore a druggable target
shared amongst the medulloblastoma subgroups. I have found that a nanoparticle formulation of the FDA-
approved CDK 4/6 inhibitor palbociclib shows reduced systemic toxicity compared to the parent drug and can
extend the survival of transgenic mice with endogenous, SHH-driven medulloblastoma. Here, I show that
palbociclib produces both the expected effect of reduced RB phosphorylation and also unexpected effects,
including a durable prolongation of S phase and an increase in OLIG2-expressing stem cells.
 I now propose in SA1 to define the mechanism of S phase alterations and identify sensitive and resistant
populations of medulloblastoma cells, using single-cell transcriptomic analysis (scRNA-seq), western blot and
immunohistochemistry. These studies will demonstrate canonical and non-canonical mechanisms of action, and
identify mechanisms of resistance that can be targeted in future studies. In SA2, I propose to test the therapeutic
efficacy of combining palbociclib therapy with the OLIG2 inhibitor CT-179. Clinical practice has shown that no
drug used as a single agent is curative for medulloblastoma, and all current treatments depend on combinations
of agents. The combination of palbociclib and CT-179 is rationally chosen based on my preliminary data.
Completing my Research Proposal and Training Plan will provide me with didactic and experiential learning
opportunities in a diverse range are approaches, from mouse genetics, to multi-dimensional cytometric assays,
to computational analysis of scRNA-seq data. This training will allow me to develop basic and translational
research skills and build a foundation for a career as an innovative, independent research scientist.

## Key facts

- **NIH application ID:** 10142133
- **Project number:** 1F31NS120459-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Taylor Yvette Dismuke
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,027
- **Award type:** 1
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142133

## Citation

> US National Institutes of Health, RePORTER application 10142133, Improving CDK 4/6 inhibition in the treatment of medulloblastoma (1F31NS120459-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10142133. Licensed CC0.

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