# MiR-155 and RUNX function in neurofibroma tumorigenesis and therapy

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $416,885

## Abstract

Principal Investigator/Program Director (Last, first, middle): Wu, Jianqiang
Project summary Using technical language, briefly describe the research design and rationale for achieving the stated goals
 Neurofibromatosis type 1 (NF1) is an inherited disease predisposing affected individuals to
benign Schwann cell tumors called plexiform neurofibromas (PNFs). Currently, prevention of PNFs is
not possible, partly because the molecular mechanisms of tumorigenesis are not fully understood.
Surgery remains the mainstay of therapy for PNFs. The FDA approved cytostatic MEK inhibitor,
Selumetinib (Koselugo), shrinks tumor in 70% of individuals but tumors regrow after stopping drug
treatment. Therefore, new therapeutic strategies and targets for the treatment of neurofibroma are
urgently needed. The endoplasmic reticulum (ER) stress response pathways play pivotal roles in
tumor growth and therapy in several cancers but remain unstudied in neurofibroma. Targeting these
ER stress pathways might provide a novel therapy for PNF patients.
 Our new preliminary data show that: a) All three ER stress signaling pathways are activated in
both mouse and human PNFs compared to controls. b) Knock down of protein kinase RNA-like
endoplasmic reticulum kinase (PERK) by shRNA decreases neurofibroma like tumor number in a cell
transplantation model in nude mice. c) Pharmacological inhibition of valosin-containing protein (VCP)
together with a MEK inhibitor (MEKi) decreases cell proliferation, increases cell apoptosis and
induces protein ubiquitination. Our central hypothesis is that loss of Nf1 in SC/SCPs leads to PNF
formation by driving Runx- and VCP-regulated proteostasis to adapt to ER stress signaling, so that
targeting proteostasis provides cytotoxic therapy for PNF patients. Two specific aims are proposed:
In aim 1, we will determine if and how Runx and VCP regulate protein synthesis and degradation to
maintain proteostasis so that Nf1-/- SC/SCPs adapt to ER stress, thereby driving PNF initiation and
growth. In aim 2, we will test whether overwhelming irresolvable ER stress by targeting VCP (alone or
in combination with MEKi) provides cytotoxic and, thus, durable control of PNF growth, and determine
the mechanism of action.
 Overall, this proposal will provide mechanistic evidence of Runx1/3 and possible VCP-
dependent proteostasis and adaptive ER stress signaling functions as oncogene on PNF formation
and provide pre-clinical rationale for MEK-independent clinical trials.

## Key facts

- **NIH application ID:** 10879080
- **Project number:** 5R01NS097233-08
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Jianqiang Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $416,885
- **Award type:** 5
- **Project period:** 2016-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879080

## Citation

> US National Institutes of Health, RePORTER application 10879080, MiR-155 and RUNX function in neurofibroma tumorigenesis and therapy (5R01NS097233-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10879080. Licensed CC0.

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