# Translation initiation as a therapeutic target in neuroblastoma

> **NIH NIH R21** · DANA-FARBER CANCER INST · 2024 · $194,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Neuroblastoma (NB) is a pediatric solid tumor of the sympathetic nervous system that accounts for 15%
of childhood cancer deaths. Tumor cell amplification of the MYCN transcription factor is seen in half of patients
with high-risk disease, where it functions as an oncogenic driver associated with metastatic disease and poor
survival. Amplified MYCN functions as a regulator of cell growth by stimulating the expression of genes that
function in ribosome biogenesis and regulatory elements of protein translation. We have identified the
translation initiation factor eIF4A, an RNA-helicase responsible for overcoming blocks to translation of 5′
untranslated regions (UTRs) to be the predominant regulator of transcript-specific mRNA recruitment in
MYCN-overexpressing NB cells. eIF4A is the primary target of the rocaglate class of protein synthesis
inhibitors, which inhibit translation initiation in a transcript-specific manner by clamping eIF4A onto
polypurine-rich (PP-rich) 5′ UTRs and preventing ribosome scanning. This unique mode of action provides
selectivity for highly proliferative cancer cells in which pro-survival transcripts are preferentially enriched in PP-
rich leaders. MYCN-associated transcripts rank highly in PP-rich 5′ UTR sequences, the majority of which
have critical roles in cell proliferation. From a library screen of amidino-rocaglates (ADRs), novel synthetic
rocaglate analogs developed by co-Investigator, Dr John Porco at Boston University, we identified a
promising candidate, CMLD012824 that disrupts eIF4A activity, thereby inhibiting translation and inducing
selective, dose-dependent cytotoxicity in MYCN-amplified NB cells. We hypothesize that ADR-mediated
inhibition of eIF4A would induce robust and selective cytotoxicity in MYCN-amplified NB cells and
would prove to be a valid therapeutic strategy in this aggressive cancer. In Aim 1, we will develop
potent, highly selective ADRs and newer guanidino-rocaglates (GDRs) that have activity against MYCN-
amplified NB cells and exhibit pharmacological properties that enable in vivo efficacy studies. In Aim 2, we
will investigate the effects of ADR/GDR inhibition in MYCN-amplified NB cell line and tumor models. The
results of these studies will provide preclinical validation of this new class of translation inhibitors for the
treatment of MYCN-amplified NB patients, and propel their development towards clinical application. Our
findings may also be relevant to other cancers that rely on transcriptional addiction and non-canonical
translation initiation mechanisms, thereby broadening the scope of this therapeutic strategy.

## Key facts

- **NIH application ID:** 10754280
- **Project number:** 5R21CA267521-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Rani E. George
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $194,750
- **Award type:** 5
- **Project period:** 2022-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754280

## Citation

> US National Institutes of Health, RePORTER application 10754280, Translation initiation as a therapeutic target in neuroblastoma (5R21CA267521-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10754280. Licensed CC0.

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