# Investigating and targeting pathways of malignant peripheral nerve sheath tumor (MPNST)

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2020 · $586,012

## Abstract

Project Abstract
Malignant peripheral nerve sheath tumors (MPNST) cause one of the highest rates of sarcoma-specific death.
Nearly half of MPNSTs arise from individuals with neurofibromatosis type 1 (NF1), representing a leading cause
of death in these patients. NF1 patients carry germline heterozygous inactivating mutations in the NF1
tumor suppressor gene. NF1 encodes a RAS-GTPase Activating Protein (RAS-GAP), a negative regulator of
RAS-mediated signaling pathways including RAF/MEK/ERK and PI3K/AKT/mTORC signaling pathways.
Inactivation of the remaining NF1 wild-type alleles drives the formation of a critical benign precursor lesion
of MPNST, plexiform neurofibroma (PNF) that is observed in 30%-50% of NF1 patients. Genetic studies have
shown that the progression of PNF-to-MPNST requires inactivation of additional pathways including (1)
inactivation of the p53 pathway, either by mutations/deletions of TP53 or CDKN2A that encodes tumor
suppressor genes INK4A and ARF, and (2) loss of the Polycomb repressor complex 2 (PRC2), by targeting
SUZ12 or EED. Despite the absence of PNFs, most non-NF1-associated sporadic and radiation-induced
MPNSTs also carry genetic alterations in these three pathways, and hence are considered as MPNST core
pathways. Despite recent progress in understanding the mechanism underlying MPNST pathogenesis, no
effective therapy is currently available except for complete surgical resection of MPNST, which is often not
feasible due to its deep location and invasive growth pattern. Thus, the development of new therapies for
MPNSTs is urgently needed. The main objective of this proposal is to investigate and target these three
MPNST core pathways as a strategy to develop novel therapies for this incurable human cancer. In Aim 1,
we will test the hypothesis that therapeutic strategies enhancing p53-mediated apoptotic responses by MEK
inhibition will present an effective therapy for CDKN2A-deficient MPNSTs with wild-type TP53. We will establish
the mechanistic basis and therapeutic efficacy of two clinically ready drugs that target these two MPNST
core pathways in a series of preclinical models of MPNSTs including low-passage cell lines, allograft and
GEM models, as well as human MPNST-derived cell lines and xenograft models. In Aim 2, we will identify
molecular mechanisms underlying PRC2 loss in the initiation, progression and therapeutic vulnerability of
MPNSTs. We will investigate a series of novel MPNST models inactivating all three MPNST core pathways and
establish the molecular basis of acquiring stem-cell characteristics by PRC2 loss-induced reprogramming or
de-differentiation during the PNF-to-MPNST transition. Our work focuses on developing therapeutic strategies
specifically for PRC2-proficient and PRC2-deficient MPNSTs.

## Key facts

- **NIH application ID:** 9952433
- **Project number:** 5R01NS115531-02
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** YUAN ZHU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $586,012
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952433

## Citation

> US National Institutes of Health, RePORTER application 9952433, Investigating and targeting pathways of malignant peripheral nerve sheath tumor (MPNST) (5R01NS115531-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952433. Licensed CC0.

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