# Targeting mTORC1 translational control in FOXO1 fusion positive rhabdomyosarcoma

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $482,175

## Abstract

PROJECT SUMMARY
PAX3-FOXO1 and related fusions create oncogenic transcription factors that remodel chromatin to drive a subset
of childhood rhabdomyosarcoma (RMS) with dismal cure rates. Therapies to target PAX3-FOXO1 are lacking.
Recently, we established mTORC1 as a PAX3-FOXO1 genetic dependency that is exploitable with third
generation bi-steric mTORC1 inhibitors, now in phase 1 testing. Unlike rapamycin, RMC-6272 prevents
mTORC1-driven assembly of eIF4F and ensuing cap-dependent translation. This corresponds to striking efficacy
in patient-derived xenografts (PDX): RMC-6272 induces prolonged remissions, while rapamycin analogs only
stabilize disease, mirroring their modest effects in patients. However, PDX eventually regrow and show
resistance to RMC-6272 re-treatment, making it clear that a knowledge gap prevents us from effectively targeting
PAX3-FOXO1 via mTORC1. What is the molecular basis for PAX3-FOXO1 “addiction” to cap-dependent
translation, and how can we rationally combine this agent to overcome resistance and enable curative therapy?
This proposal addresses these questions with the goal of providing a molecularly informed strategy to aid
ongoing clinical development of bi-steric mTORC1 inhibitors in childhood cancer.
Aim 1 will define the molecular basis for RMC-6272 efficacy in fusion positive RMS. Excitingly, informatic
and proteomic data lead us to the anchoring hypothesis that PAX3-FOXO1 requires cap-dependent translation
for its own expression. We will use precise biochemical assays of mRNA translation and protein synthesis to test
this. Building on the observation that patient-derived xenografts (PDX) driven by less frequent PAX7-FOXO1
fusions show reduced response to RMC-6272, we will define molecular features in the untranslated regions
(UTRs) of PAX3 and PAX7 fusions that require mTORC1 and eIF4F for their translation, and test whether UTR
sequence determines RMC-6272 efficacy. Aim 2 will define the best means to augment RMC-6272 efficacy
in PDX. Single agents are rarely successful in curing even genetically simple cancers like fusion positive RMS,
and indeed we observe the emergence of resistance to RMC-6272 monotherapy. We find that BET inhibitors
(which decrease PAX3-FOXO1 expression) and RAS inhibitors (which blunt feedback activation of MAPK) each
are synergistic with RMC-6272. We hypothesize that such mechanism-based combinations will offer curative
treatment and will compare them to combinations with chemotherapy that are the mainstay of relapsed RMS
studies. Using pharmacodynamic modeling in PDX, we will identify safe and optimal biologic dosing to combine
agents, then find the strategy that best prolongs survival and prevents resistance to translate into clinical trials.
Completion of these aims will detail how eIF4F orchestrates oncogene output in a frequently lethal pediatric
cancer and define strategies to further enhance these effects to offer curative treatment. Beyond guiding bi-steric
mTORC1 inhibitor use in...

## Key facts

- **NIH application ID:** 10979766
- **Project number:** 1R01CA285680-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Amit J. Sabnis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $482,175
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979766

## Citation

> US National Institutes of Health, RePORTER application 10979766, Targeting mTORC1 translational control in FOXO1 fusion positive rhabdomyosarcoma (1R01CA285680-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10979766. Licensed CC0.

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