# Remodeling the translatome in N-myc mediated medulloblastoma and its therapeutic implications

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $666,183

## Abstract

Medulloblastoma is the most common malignant pediatric brain tumor. After surgery, radiation and
chemotherapy, five-year survival is 60-70% overall. Survivors show severe physical and cognitive disabilities,
often unable to live independently. Medulloblastoma exists in four distinct molecular subgroups (WNT, SHH,
Group3, Group 4). An incurable subgroup of SHH driven tumors show amplification of the MYCN transcription
factor. How can we target N-myc in medulloblastoma? N-myc’s ability to regulate protein synthesis is tied both
to its oncogenic potential and to interactions with the mTOR serine-threonine kinase. We hypothesize that N-
myc hijacks the translational machinery regulated by the mTOR serine threonine kinase to drive transformation;
and that targeting translation control represents a therapeutic strategy for N-myc driven cancers. Employing
ribosome profiling technology, we surprisingly found that in addition to roles as a global regulator of protein
synthesis, N-myc interacts with mTOR to regulate translation of 13 mRNAs belonging to the folding machinery,
functionally important for N-myc driven medulloblastoma. The mechanisms by which N-myc directs the
translation of these specific subsets of mRNAs to drive tumorigenesis and whether these potential vulnerabilities
can be leveraged to develop targeted therapies remain outstanding questions. In this proposal, we will
mechanistically dissect how N-myc hijacks the translational machinery for its oncogenic activity. Using novel
genetic approaches, we will separately evaluate the importance of eIF4E and eIF4A in our N-myc driven
genetically engineered mouse (GEM) models. We will also test new clinical drugs against eIF4A and eIF4E,
analyzing GEM models, and patient derived orthotopic xenografts. Successful completion of these aims will
delineate how N-myc interacts with mTOR to regulate key subsets of translational targets, and elucidates
druggable mechanisms in N-myc driven medulloblastoma.

## Key facts

- **NIH application ID:** 10522626
- **Project number:** 1R01NS125668-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Davide Ruggero
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $666,183
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522626

## Citation

> US National Institutes of Health, RePORTER application 10522626, Remodeling the translatome in N-myc mediated medulloblastoma and its therapeutic implications (1R01NS125668-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10522626. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*