# Improving Therapeutic Approaches for RAS-driven Rhabdomyosarcoma

> **NIH NIH R37** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $195,227

## Abstract

Summary
Despite the use of aggressive chemo-radiation therapy, children with high-risk rhabdomyosarcoma (RMS)
including advanced or metastatic embryonal RMS (ERMS) with RAS mutations, have very poor outcomes (20-
30% survival at 5 years from diagnosis) with no significant improvement over the last 30 years. Further, current
multimodality therapies are associated with life-long life-threatening sequelae. This project focuses on
developing less-genotoxic, targeted therapy for RAS-mutant ERMS. Preliminary data support rapid translation
of vertical targeting of the MAPK pathway as a therapeutic approach in ERMS. The proposed aims are based
upon the following observations: (i) In RAS-driven ERMS, resistance to MEK inhibitors is a consequence of
pathway reactivation through CRAF; (ii) Combination of new generation type 2 RAF inhibitors with MEK inhibitors
cause dramatic regressions of most RAS-mutant ERMS PDX models but are not curative. Consequently, both
intrinsic and acquired resistance will be a barrier for long-term curative outcomes; (iii) Innovative single mouse
testing (SMT) experimental design shows that, consistent with their high-risk classification, RAS-mutant ERMS
PDX/CDX models, rapidly fail intensive multidrug regimens used in the most recent high-risk RMS clinical
protocol (ARST0431). Therefore, this project aims to: 1) define mechanisms of innate and acquired resistance
to co-targeting RAF and MEK in RAS-driven ERMS with the goal to facilitate more impactful clinical outcomes.
Using DNA and RNA sequencing, we will identify genomic/epigenomic changes associated with resistance and
validate and define mechanisms of innate and acquired resistance to combining type 2 RAF and MEK inhibitors
in ERMS; 2) evaluate how this approach can be integrated into current clinical chemotherapy protocols using
the SMT experimental design. Our studies will inform biomarkers of response to type 2 RAF + MEK inhibitors
combination and how this combination can be sequenced relative to chemotherapy to optimize responses of
RMS PDX/CDX models, thus directly impacting clinical trials design for RAS-driven ERMS.

## Key facts

- **NIH application ID:** 11116323
- **Project number:** 7R37CA262657-04
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Angelina V Vaseva
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,227
- **Award type:** 7
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11116323

## Citation

> US National Institutes of Health, RePORTER application 11116323, Improving Therapeutic Approaches for RAS-driven Rhabdomyosarcoma (7R37CA262657-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11116323. Licensed CC0.

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