# Transporters and Medulloblastoma

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $406,501

## Abstract

Abstract
Improving the survival of children with central nervous system (CNS) cancers, especially brain cancers such as
medulloblastoma (MB), the most frequent CNS cancer in children, will require overcoming two therapeutic
barriers: the blood brain barrier (BBB) and blood tumor barrier (BTB). Medulloblastoma (MB), a malignant
pediatric brain tumor of the cerebellum, is the most common brain tumor and leading cause of non-accidental
death in children and adults, especially children under 5 years. Overall the Group 3 (G3) subtype of MB has the
worst overall prognosis, expresses the ABC transporter, ABCG2, and are the most difficult to treat. High
expression of ABCG2 in G3 MB is associated with poor overall survival. We have shown in a pre-clinical murine
model of G3 MB (that faithfully recapitulates the human disease) that ABCG2 in the tumor (the BTB) remains an
obstacle to effective therapy. ABCG2's high expression at the BBB also limits the therapeutic effectiveness of
many active CNS medications. Overcoming ABCG2 activity by more than competitive inhibition is a desirable
strategy and likely to provide a more durable suppression of ABCG2 activity and consequently improvement in
chemotherapeutic efficacy. Our promising preliminary data shows that we have developed a novel ABCG2
pharmacophore model and used this to identify a new ABCG2 inhibitor that promotes ABCG2 loss of function by
activating retrieval from the membrane. The membrane retrieval of ABCG2 appears to be initiated by a specific
protein interaction that is driven by the inhibitor because removal of the inhibitor results in loss of the protein
interaction. We propose three complementary Aims that encompass studies that will mechanistically elucidate
how this new inhibitor not only initiates the retrieval of ABCG2 from the membrane, but also determines its
efficacy compared to a conventional ABCG2 inhibitor. The aims will: 1) test the hypothesis that ABCG2 inhibition
can be driven by loss of membrane localization. 2) elucidate the genetic and molecular pathway by which the
inhibitor promotes ABCG2 membrane retrieval. 3) determine if the novel ABCG2 inhibitor is more effective than
conventional inhibitors in improving the chemotherapeutic efficacy in G3 MB. The knowledge from this project
will have important therapeutic implications and promote improved strategies for treating children with G3 MB.

## Key facts

- **NIH application ID:** 10211921
- **Project number:** 2R01CA194057-06A1
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** JOHN D SCHUETZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $406,501
- **Award type:** 2
- **Project period:** 2015-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211921

## Citation

> US National Institutes of Health, RePORTER application 10211921, Transporters and Medulloblastoma (2R01CA194057-06A1). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10211921. Licensed CC0.

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