# Studies of the structural and functional basis of neuroblastoma drug resistance

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $51,752

## Abstract

PROJECT SUMMARY/ABSTRACT
 Neuroblastoma is the most common extracranial tumor of young children, and the five-year overall
survival of children with high-risk disease is less than 50%. Overexpression of multidrug resistance protein 1
(MRP1), a plasma membrane ATP-binding cassette (ABC) transporter, is associated with high-risk
neuroblastoma. MRP1 transports multiple neuroblastoma chemotherapeutic agents out of the cell in a
glutathione (GSH)-dependent manner. Other MRP1 substrates are transported in a GSH-independent manner,
and certain compounds stimulate MRP1-mediated GSH efflux without being transported themselves. The
mechanisms of GSH-dependent and GSH-independent MRP1 substrate transport – as well MRP1-mediated
GSH efflux – are still not well understood. Specific Aim 1 of this proposal seeks to determine the structural basis
of GSH-dependent vs. GSH-independent substrate transport by MRP1 using cryo-electron microscopy coupled
with biophysical, biochemical, and cell-based assays for MRP1 function. Specific Aim 2 of this proposal seeks
to determine the structural basis of the activation and inhibition of GSH efflux by ligands that regulate MRP1
activity. The successful completion of these aims will fill a gap in the research literature by determining the
structural basis for MRP1 substrate poly-specificity, particularly with respect to chemotherapeutic agents used
in the treatment of neuroblastoma, and will provide a basis for future therapeutic intervention.
 The proposed research strategy will be completed under the mentorship of Dr. Jue Chen in the Laboratory
of Membrane Biology and Biophysics at The Rockefeller University in New York City. The accompanying
fellowship training plan will be completed through the Tri-Institutional MD-PhD Program of Weill Cornell Medicine,
The Rockefeller University, and Memorial Sloan Kettering Cancer Center. The exceptional clinical and scientific
resources of these environments will facilitate the successful completion of both research and training
components. The biochemical, biophysical, and structural biology equipment and expertise available at The
Rockefeller University is unparalleled, and trainees are also encouraged to collaborate with other scientists and
institutions in New York City’s rich structural biology research network. The Tri-Institutional MD-PhD Program
offers a diversity of clinical, research, and extracurricular opportunities for trainees to develop the analytical,
technical, communication, and mentoring skills necessary to become an independent physician-scientist.
Trainees are encouraged to continuously develop their clinical and scientific skills throughout both medical and
graduate phases of the MD-PhD curriculum. This curriculum is supervised by a supportive administration that
provides ample guidance for trainees to pursue productive careers promoting the health of the American public.

## Key facts

- **NIH application ID:** 10323652
- **Project number:** 5F30CA257282-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Harlan Linver Pietz
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10323652

## Citation

> US National Institutes of Health, RePORTER application 10323652, Studies of the structural and functional basis of neuroblastoma drug resistance (5F30CA257282-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10323652. Licensed CC0.

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