# Elucidating the Role of Epigenetic Plasticity in anti-GD2 Immunotherapy Response

> **NIH NIH F32** · DANA-FARBER CANCER INST · 2022 · $69,674

## Abstract

Project Summary
Ganglioside GD2 is expressed on the cell surface of numerous pediatric cancers, including Ewing sarcoma,
osteosarcoma, and neuroblastoma. In 2015, FDA approval of the anti-GD2 immunotherapy dinutuximab
represented a paradigm shift in the treatment of neuroblastoma by significantly reducing the incidence of tumor
recurrence. Despite dinutuximab's success, dinutuximab fails ~30% of neuroblastoma patients. Reports
suggest that the degree of surface GD2 expression correlates with clinical response to dinutuximab. However,
the cellular mechanisms governing GD2 regulation in tumor cells remain unknown. Correlation of surface GD2
expression with RNA-sequencing in a large cohort of neuroblastoma cell lines revealed that GD2 expression is
associated with a mesenchymal epigenetic program. Epithelial-to-Mesenchymal Transition (EMT) has been
widely studied in epithelial solid tumors for its purported role in chemoresistance. However, there have been
no reports linking an adrenergic-to-mesenchymal transition (AMT) epigenetic program to regulation of surface
antigen GD2, making this relationship of intense interest to the neuroblastoma community. In this proposal,
AIM 1 will elucidate the relationship between AMT and GD2 expression by rigorously testing the sufficiency
and necessity of the neuroblastoma-specific AMT transcription factor PRRX1 to regulate GD2. Further, loss of
GD2 expression via AMT will be tested in vitro and in vivo for loss of response to dinutuximab. Aim 2 will
evaluate the pathways underlying loss of GD2 expression. Preliminary data suggest that mesenchymal cell
lines and tumors express markedly reduced GD3 synthase via epigenetic silencing at the gene promoter. We
will evaluate whether AMT directly regulates GD3 synthase, and whether restoration of its expression rescues
response to dinutuximab. These findings will directly link epigenetic state to the downregulation of tumor
antigen GD2 and response to dinutuximab. Further, these studies may help inform rational combinatorial
strategies to enhance anti-GD2 therapies in neuroblastoma, and could provide a framework for future studies
in other GD2-expressing pediatric cancers.

## Key facts

- **NIH application ID:** 10400577
- **Project number:** 5F32CA261035-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Nathaniel Mabe
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $69,674
- **Award type:** 5
- **Project period:** 2021-06-01 → 2023-05-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400577

## Citation

> US National Institutes of Health, RePORTER application 10400577, Elucidating the Role of Epigenetic Plasticity in anti-GD2 Immunotherapy Response (5F32CA261035-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10400577. Licensed CC0.

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