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PubMed2026

Combination of EZH2 and MEK inhibitors as an effective therapy for neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

BACKGROUND: Neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with poor outcomes and limited therapeutic options. Although mitogen-activated protein kinase kinase (MEK) inhibitors are active in benign plexiform neurofibromas, their efficacy in MPNST treatment is modest. Enhancer of zeste homolog 2 (EZH2) inhibitors are preclinically efficacious in MPNST treatment, but their mechanisms of action remain unclear. We evaluated the therapeutic potential and molecular mechanism of combined EZH2 and MEK inhibitors in NF1-associated MPNST. METHODS: Five human NF1-associated MPNST cell lines were exposed to EZH2 and/or MEK inhibitors. Cell growth and apoptosis were quantified over time. Therapeutic efficacy was tested in a subcutaneous xenograft model. Proliferation and apoptosis in tumors were assessed using standard histologic markers, and intracellular localization of phosphorylated extracellular signal-regulated kinase (pERK) was examined using fluorescent immunohistochemistry. RESULTS: Monotherapy with EZH2 or MEK inhibitors reduced proliferation and increased apoptosis across all MPNST lines. Combination therapy produced greater tumor cell growth suppression and marked increases in apoptosis. In vivo, the combination significantly delayed tumor progression compared with monotherapy, with concomitant reductions in proliferative indices and increases in apoptotic indices. EZH2 inhibitor limited nuclear pERK entry. CONCLUSIONS: Dual EZH2 and MEK inhibitors yield additive antitumor activity in NF1-associated MPNST. Although the molecular mechanism could not be elucidated, our findings suggest that EZH2 inhibitors exhibited a polycomb repressive complex 2-independent, noncanonical mechanism characterized by pERK nuclear translocation restriction, providing a strong rationale for clinical evaluation of this combination in NF1-associated MPNST.

EZH2 inhibitor↗

PubMed2026

Personalized medicine strategy for MPNSTs: using precision oncology on PDOX models to inform tumor boards.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are a heterogeneous group of aggressive soft tissue sarcomas with poor prognosis. Currently there is a lack of effective treatments for MPNSTs. Here, we propose a personalized medicine approach that integrates a precision oncology strategy guided by MPNST genomic analysis, with a functional validation of treatment response in an orthotopic xenograft model (PDOX) derived from the same MPNST. METHODS: Comprehensive whole genome sequencing analysis was performed in primary MPNSTs, relapses and (in one case) metastases, following disease progression in two independent individuals. Matched MPNST PDOX models were generated by orthotopically implanting tumor fragments near the sciatic nerve of immunodeficient mice. Candidate targeted combination therapies were prioritized based on genomic alterations and tested in vivo in the PDOX models. RESULTS: The feasibility of the developed strategy is illustrated for two MPNST patients, one Neurofibromatosis type 1 (NF1) individual that developed two independent MPNSTs and another sporadic MPNST case with multiple metastatic relapses. Genomic analysis revealed a remarkable degree of genomic stability across primary MPNSTs and their successive relapses in each patient, and even metastases in one individual. While based on a small number of cases requiring additional analyses, this finding aligns with previous evidence suggesting a fair genomic conservation throughout tumor evolution. This stability supports the identification of consistent therapeutic vulnerabilities throughout disease progression. Among the therapies tested, co-treatment of MEK inhibitor (MEKi) plus bromodomain inhibitor (BETi) elicited the highest antitumor activity, resulting in approximately 60% tumor volume reduction in the sporadic MPNST PDX model, whose patient has been receiving this therapy for eight months with sustained remission. CONCLUSIONS: This study demonstrates the feasibility and clinical utility of integrating genomic-driven precision oncology with PDOX-based functional testing for MPNSTs. This strategy may support molecular tumor boards (MTBs) in their treatment decisions. The observed genomic stability supports the use of longitudinal tumor profiling to guide treatment, and the success of MEKi+BETi highlights its potential as a combination therapy for MPNSTs.

Precision Medicine↗

PubMed2026

Molecular subgroups of human malignant peripheral nerve sheath tumors are conserved in canines.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas of Schwann cell lineage with poor prognosis in both humans and dogs. While rare in humans, MPNSTs occur more frequently in dogs and share histomorphological and clinical features. Recent methylome and transcriptome analyses have identified two molecular subgroups of human MPNST with distinct oncogenic signaling pathways and prognostic implications; however, it remains unclear if these subgroups also exist in canines. Given their higher incidence and biological similarities to human disease, canine MPNSTs represent a promising comparative model to investigate molecular subtypes and evaluate novel therapeutic strategies. To characterize canine MPNST and assess molecular parallels with the human subgroups, we applied laser-capture microdissection (LCM) followed by RNAsequencing to analyze tumor tissue from 20 canine MPNST. Principle component and differential gene expression analyses identified two clearly distinct transcriptional clusters corresponding to spindle cell and epithelioid MPNST variants, respectively. Unsupervised cross-species comparison aligned the two canine clusters with the human G1 and G2 subgroups. Accordingly, one cluster was characterized by SHH pathway activation and increased cell cycle activity, while the other showed non-canonical WNT pathway, Schwann cell-like features and marked macrophage infiltration. Immunohistochemistry further demonstrated loss of H3K27me3, p-ERK activation and β-catenin signaling by IHC in a subset of tumors. These findings support the value of canine MPNST as clinically amenable model for structured assessment of novel therapeutic approaches to benefit patients of both species.

Canine cancer model↗

PubMed2025

Integrated genomic analysis of NF1-associated peripheral nerve sheath tumors: an updated biorepository dataset.

Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous condition that predisposes to the development of peripheral nerve sheath tumors (PNST) including cutaneous neurofibromas (CNF), plexiform neurofibromas (PNF), atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP), and malignant peripheral nerve sheath tumors (MPNST). The Johns Hopkins NF1 biospecimen repository promotes the successful advancement of therapeutic developments for NF1-associated PNST through acquisition and genomic analysis of human tumor specimens. RNA sequencing (RNAseq) and whole exome sequencing (WES) data were generated from 73 and 114 primary human tumor samples, respectively. These pre-processed data, standardized for immediate computational analysis, are accessible through the NF Data Portal, allowing immediate interrogation. This dataset combines new and previously released samples, offering a comprehensive view of the entire cohort sequenced. As a dedicated effort to systematically bank tumor samples from people with NF1, in collaboration with molecular geneticists and computational biologists, the Johns Hopkins NF1 biospecimen repository offers access to tissue samples and genomic data to promote the advancement of NF1-related tumor biologic insights and therapies.

Humans↗