# Therapeutic degradation of Capicua (CIC) fused oncoproteins in undifferentiated sarcomas

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $369,431

## Abstract

PROJECT SUMMARY/ABSTRACT
The CIC-DUX4 fusion oncoprotein is the molecular hallmark of a highly lethal subset of undifferentiated
sarcomas that affects children, adolescents, and young adults (AYA). We have recently revealed critical
transcriptional programs downstream of CIC-DUX4 that drive malignant phenotypes, including tumor growth
and metastasis. Additionally, recent studies demonstrate that Capicua (CIC) protein expression is directly
modulated by the mitogen-activated protein kinase (MAPK)-signaling pathway. The long-term goal of our
laboratory is to identify and dissect the critical molecular pathways that regulate fusion oncoprotein stability and
expression in human sarcoma. Our studies will reveal fusion oncoprotein-specific vulnerabilities that can
facilitate precision-based therapeutic design to improve outcomes for patients with universally lethal forms of
sarcomas. The objective of this proposal is to fuse our expertise in Capicua (CIC) biology and MAPK signaling
to develop the first precision-based therapeutic approach for CIC-DUX4 sarcomas. We hypothesize, that
genetic or pharmacologic MAPK activation will lead to the degradation of the CIC-DUX4 oncoprotein. Our
rationale is based on our prior studies demonstrating MAPK-mediated regulation of wild-type (non-fused) CIC
protein expression in the context of human cancer. Our specific aims will test the following hypotheses: (Aim 1)
human ERK physically interacts with nuclear CIC-DUX4; (Aim 2) MAPK-ERK pathway activation decreases
CIC-fused oncoprotein stability, leading to degradation; and (Aim 3) pharmacologic activation of the MAPK
pathway decreases tumor cell survival through rapid degradation of the CIC-DUX4 fusion oncoprotein. The
significance of these findings are highly impactful, as there are no effective therapeutic strategies to target CIC-
DUX4 sarcomas, which remain lethal in the metastatic setting. Our proposal is innovative because we are
leveraging our expertise in MAPK-signaling, transcription factor fusions, and Capicua biology to develop a
precision-based therapeutic approach to directly target and degrade a lethal fusion oncoprotein in sarcoma, an
unmet scientific and clinical need.

## Key facts

- **NIH application ID:** 10434138
- **Project number:** 5R37CA255453-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ross Okimoto
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $369,431
- **Award type:** 5
- **Project period:** 2021-06-17 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434138

## Citation

> US National Institutes of Health, RePORTER application 10434138, Therapeutic degradation of Capicua (CIC) fused oncoproteins in undifferentiated sarcomas (5R37CA255453-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434138. Licensed CC0.

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