# Targeting leptomeningeal metastasis in medulloblastoma

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $490,282

## Abstract

Medulloblastoma (MB) is the most common malignant childhood brain tumor. Even with aggressive therapy,
many patients still die of their disease. Moreover, survivors suffer severe long-term side effects as a result of
treatment, which are thought to result in large part from radiation-induced damage to the developing nervous
system. Unlike other brain tumors, which infiltrate through the brain parenchyma, MB commonly spreads
through the meninges that surround the brain and spinal cord, a phenomenon termed leptomeningeal
metastasis (LM). We recently performed a high throughput drug screen to identify the polypeptide antibiotic
actinomycin as a compound of interest for the treatment of MB. We developed methods to encapsulate
actinomycin within biodegradable and biocompatible polymeric nanoparticles. We have also identified a
peptide ligand capable of targeting receptors that are upregulated on both spinal cord vasculature and patient
derived MB. Our preliminary data demonstrate that actinomycin delivered from nanoparticles is significantly
more effective at treating intracranial MB than free drug when administered intravenously. Further, we
demonstrate that nanoparticles administered directly to the cerebrospinal fluid (CSF) localize with malignant
cells to slow the growth of LM. In this work, we will evaluate delivery strategies (presence of targeting ligand,
route of administration) to optimize these new approaches in MB. Nanoparticles will be "barcoded" to fluoresce
in distinct wavelengths, such that the cellular level distribution of both control and targeted nanoparticle
formulations can be evaluated within a single subject to directly assess nanoparticle fate and drug action at the
cellular level. We will test test these systems in patient derived and genetically engineered models of MB
exhibiting LM. We hypothesize that improved, targeted nanoparticle delivery will enhance exposure of
metastatic cells to drug, to improve therapeutic efficacy and reduce the radiation dose needed to achieve
complete tumor therapy. To test this hypothesis, we will (1) track delivery of targeted nanoparticles to
malignant cells in the brain and spinal cord; (2) evaluate delivery, activity, and toxicity of actinomycin; and (3)
test efficacy of targeted therapies in combination with radiation. Our experimental approach has been designed
to sequentially refine the design of drug-loaded nanoparticles to yield a better treatment for MB by directly
addressing LM as a unique disease burden. We expect that the outcome of these studies will also yield new
strategies for spinal cord targeted drug delivery that will be relevant to other disseminated cancers or
neurological diseases affecting the spinal cord.

## Key facts

- **NIH application ID:** 9917838
- **Project number:** 5R01NS111292-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Rachael W Sirianni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,282
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917838

## Citation

> US National Institutes of Health, RePORTER application 9917838, Targeting leptomeningeal metastasis in medulloblastoma (5R01NS111292-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9917838. Licensed CC0.

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