RARE DISEASE
Malignant peripheral nerve sheath tumor
Malignant peripheral nerve sheath tumor
Malignant peripheral nerve sheath tumor
Synonyms: MPNST, Malignant neurilemmoma, Malignant neurofibroma, Malignant schwannoma, Neurofibrosarcoma, Neurogenic sarcoma
Synonyms: MPNST, Malignant neurilemmoma, Malignant neurofibroma, Malignant schwannoma, Neurofibrosarcoma, Neurogenic sarcoma
Synonyms: MPNST, Malignant neurilemmoma, Malignant neurofibroma, Malignant schwannoma, Neurofibrosarcoma, Neurogenic sarcoma
Drug discovery
1
drug
With orphan designation
Overview
Malignant peripheral nerve sheath tumor (MPNST) is a rare, aggressive soft tissue sarcoma arising from peripheral nerve sheaths, often linked to neurofibromatosis type 1 (NF1) or prior radiation [1][8][14]. Characterized by rapid growth, high recurrence rates (~40%), and frequent metastasis (commonly to lungs), it has a poor prognosis (5-year survival: 30-50%) [3][12][16]. Diagnosis relies on imaging (MRI/CT) and biopsy, while treatment emphasizes surgical resection with adjuvant radiotherapy; chemotherapy offers limited benefit in advanced disease [7][19][20].
Population
Annual incidence of 1.0-1.26 per million; 50% associated with NF1 (lifetime risk: 8-13%) [1][14][16].
Highest incidence in Black individuals vs. White/Asian groups; median diagnosis age 30-50 [2][6][12].
Gender distribution varies (slight male predominance in some studies, female in others) [2][14][18].
Therapies
Categories: rare neoplastic diseases, rare neurological diseases
Research Papers
1,021 drug discovery papers about Malignant peripheral nerve sheath tumor, with 4 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,021 drug discovery papers about Malignant peripheral nerve sheath tumor, with 4 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-18 | PRC2 loss in MPNST is accompanied by SWI/SNF complex rewiring and sensitization to SMARCA2/4 and BET inhibition in vivo.
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas of peripheral nerve sheath that frequently arise in patients with neurofibromatosis type 1 (NF1) and currently have no approved targeted treatment. Loss of Polycomb Repressive Complex 2 (PRC2) activity, through inactivating mutations in SUZ12 or EED, occurs in 50 to 80% of NF1-associated MPNSTs, leads to depletion of H3K27me3 in cells, global epigenetic dysregulation, and serves as an indicator of poor clinical outcomes. SWI/SNF (BAF) complexes are ATPase-driven chromatin remodelers essential for orderly transcriptional activity in cells. Because PRC2 and SWI/SNF enforce functionally antagonistic effects on chromatin, we hypothesized that PRC2-deficient MPNSTs undergo alterations in the SWI/SNF complex that create a therapeutic vulnerability to SWI/SNF inhibition. We performed integrated proteogenomic profiling of patient-derived MPNST cell lines stratified by PRC2 status: Loss of Function (LoF) or Wild Type (WT). We found that PRC2 loss in MPNST was associated with broad reduction in global SWI/SNF protein abundance, recurrent enrichment of SMARCD3 in SMARCA4-containing complexes, and context-dependent enrichment of DPF3 and PBAF-specific subunits. ChIP-seq analyses showed redistribution of cBAF and PBAF chromatin occupancy in PRC2 LoF models followed by concordant increases in H3K27ac signal and gene expression. Cell fitness assays revealed that the SWI/SNF ATPase inhibitor, FHD-286, reduced cell viability in PRC2 LoF MPNST lines at low nanomolar concentrations and disrupted the colony forming ability, while PRC2 WT cell lines were less sensitive to treatment. Finally, evaluating the efficacy of FHD-286 alone, and in combination with I-BET-762, in an isogenic PRC2 loss murine allograft MPNST model, we observed enhanced efficacy of the combination regimen compared to either single agent in the Suz12 KO arm, while in the Suz12 WT arm, the combo was outperformed by I-BET-762 alone. Together, our findings indicate that PRC2 loss in MPNST is accompanied by selective subunit remodeling and genomic redistribution of SWI/SNF complexes and support SWI/SNF ATPase inhibition, alone and in combination with BET inhibition, as an attractive therapeutic strategy for PRC2-deficient MPNSTs.
2026-09-13 | 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.
2026-09-11 | RBPMS::NTRK3-rearranged sacral malignant spindle cell tumor in neurofibromatosis diagnosed by RNA sequencing: a case report and literature review.
Malignant spindle cell tumors arising in patients with neurofibromatosis are diagnostically challenging because malignant peripheral nerve sheath tumor (MPNST) and emerging NTRK-rearranged mesenchymal neoplasms may show overlapping clinical, histological, and immunophenotypic features. We report a 31-year-old man with a more than 20-year history of neurofibromatosis who presented with progressive lumbosacral pain and left lower-limb numbness. Imaging revealed a large cystic-solid sacral mass involving the S1-S2 region and extending through the sacral foramina into the pelvis. Core needle biopsy showed an intermediate-grade malignant spindle cell tumor with partial CD34 expression, strong pan-TRK positivity, increased p53 expression, and a Ki-67 labeling index up to 50% in hotspot areas. NTRK1 break-apart fluorescence in situ hybridization (FISH) was negative; however, RNA-based next-generation sequencing identified an RBPMS::NTRK3 fusion, establishing a molecularly confirmed NTRK3-rearranged spindle cell neoplasm and explaining the pan-TRK positivity as a true-positive result. The negative NTRK1 FISH reflected involvement of NTRK3 rather than NTRK1, illustrating that single-gene FISH cannot exclude an NTRK fusion. Given the large local tumor burden, neurological symptoms, high surgical morbidity, and the confirmed actionable fusion, the patient received molecularly guided entrectinib combined with palliative radiotherapy, with marked pain relief, neurological improvement, and radiological tumor shrinkage; at the most recent follow-up, approximately 7 months after starting entrectinib, he remained without evidence of disease progression. This case underscores that pan-TRK positivity should prompt confirmatory RNA-based sequencing rather than reliance on single-gene FISH; that actionable NTRK fusions may occur in the neurofibromatosis setting, where MPNST is the principal differential; and that molecularly informed multimodal therapy can benefit anatomically complex tumors, although response attribution requires caution when targeted therapy and radiotherapy are combined.
2026-09-09 | Combination of EZH2 and MEK inhibitors as an effective therapy for neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.
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. 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. 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. 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.
2026-09-01 | Ornithine decarboxylase levels in peripheral nerve sheath tumors from NF1 patients.
The study was conducted to determine the level of ornithine decarboxylase (ODC) activity in several types of peripheral nerve sheath tumors to assess ODC as a potential target for alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. A formalin-fixed paraffin-embedded peripheral nerve sheath tumor tissue microarray was developed in the Department of Anatomic Pathology, MD Anderson Cancer Center. ODC levels were measured using immunofluorescence with a polyclonal antibody to ODC and Alexa-Fluor 647 goat anti-rabbit IgG using previously validated and established methodology. Nuclear and cytoplasmic ODC levels were assessed to determine surrogate ODC activity based on immunofluorescence from 11 patients with a spectrum of nerve sheath tumors, including malignant peripheral nerve sheath tumors (MPNSTs), plexiform neurofibroma, WHO Grade 1 (NF), atypical neurofibroma neoplasm of uncertain biologic potential (ANNUBP), and schwannoma. ODC activity was less than 5 nmol/30 min/min/ug ODC protein in many MPNST, NF, and schwannomas, but higher than 10 nmol/min/ug protein in ANNUBP tumors and one NF tumor. Nuclear ODC activity varied across peripheral nerve sheath tumors, with relatively low to moderate levels observed in MPNSTs and higher levels in ANNUBP tumors within the small cohort studied. Since DFMO, an irreversible ODC inhibitor, is more effective in slow-growing grade 2 and 3 gliomas with low ODC levels than in higher malignancy grade 4 glioma with high ODC activity, it is reasonable to assume that MPNSTs and neurofibromas, WHO grade, with relatively low to moderate levels of ODC activity may be suitable candidates for DFMO therapy. However, larger studies are needed to validate ODC activity as a predictive biomarker and to determine the therapeutic efficacy of DFMO in peripheral nerve sheath tumors.
gene therapies
2025-11-26 | Challenges and Progress for Treatment of Malignant Peripheral Nerve Sheath Tumors in the Context of Recent Successes for Sarcoma Therapy
Malignant peripheral nerve sheath tumors (MPNSTs) are one of the most difficult sarcomas to treat. Due to the rarity of MPNSTs, many of the therapeutic approaches used are from treatment guidelines for soft tissue sarcoma. Besides surgery, little success has been achieved using these therapies. Traditional chemotherapy and radiation therapy regimens designed to treat sarcoma have unclear efficacy when used to treat MPNSTs. Targeted therapeutics that succeeded in other sarcomas failed to produce positive results in MPNSTs. Moreover, investigational agents that have shown efficacy in preclinical models have produced disappointing outcomes in clinical trials. While therapeutic options for patients with MPNST have remained relatively stagnant, dramatic improvements in therapeutic outcomes of other rare sarcomas have been made. This difference in success is likely caused by the complex heterogeneity of MPNSTs that hinders drug development, although many MPNSTs are associated with neurofibromatosis type 1 (NF1), a genetic disorder resulting from mutations in the NF1 gene that encodes the negative RAS regulator neurofibromin. The development of new agents for MPNST treatment has shifted away from solely targeting RAS pathway gene products to stimulating the immune system and manipulating other MPNST driver mutations such as CDKN2A/B, SUZ12, EED, and TP53. This review presents recent advances in the treatment of sarcomas and the future of drug development targeting MPNSTs.
2025-11-26 | Neurofibromatosis Type 1: Genetic Mechanisms and Advances in Therapeutic Innovation
Mutations in the NF1 gene cause Neurofibromatosis Type 1 (NF1), one of the most common genetic disorders. This gene encodes neurofibromin, a member of the GTPase-activating protein (GAP) family that functions as a negative regulator of RAS signaling. Loss of NF1 function leads to persistent RAS activation and promotes tumor growth. The clinical manifestations of NF1 mainly include pigmentary changes, benign and malignant peripheral nerve sheath tumors, as well as gliomas affecting the central nervous system. Currently, MEK inhibition is the only approved therapy and is primarily effective in controlling plexiform neurofibromas (pNFs). However, more comprehensive treatments are needed to address the full spectrum of NF1 manifestations and malignant transformation. Novel therapeutic strategies, including AAV-based gene therapy aimed at restoring NF1 function, oncolytic herpes simplex virus (oHSV) therapy targeting RAS-dysregulated tumor cells, and chimeric antigen receptor T cell (CAR-T) therapy targeting NF1-associated tumors, are under active investigation. In this review, we explore the genetic mechanisms underlying NF1 and highlight recent advances in therapeutic development with a special focus on AAV-based gene therapies alongside other approaches with recent clinical and translational advancements.
2025-09-30 | Development of an adeno-associated virus vector for gene replacement therapy of NF1-related tumors.
Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome caused by alterations in NF1 gene that lead to tumor growth throughout the nervous system, which can cause morbidity and mortality, and transform to malignancy. NF1 gene replacement therapy, though promising, is hindered by NF1 gene's large size and delivery challenges. We introduced a membrane-targeted, truncated neurofibromin comprising the GAP-related domain (GRD) fused to the KRAS4B C-terminal domain, which effectively inhibits the RAS signaling pathway and restores Schwann cell differentiation in an NF1 iPSC-derived model. For systemic application, we engineered an adeno-associated virus (AAV) vector using in vivo capsid evolution through sequential DNA shuffling and peptide library screening in a NF1 xenograft mouse model. This tailored vector, AAV-NF, exhibits greatly reduced liver uptake, enhanced tumor targeting across various NF1-related MPNST, neurofibromas and glioma models, and therapeutic efficacy in xenografts of MPNST. This study not only advances a viable AAV vector for NF1 treatment but also outlines a replicable strategy for vector and payload development in other monogenic and tumor-associated disease manifestations.
2024-07-09 | Corrigendum: Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors
Corrigendum: Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors
2024-06-19 | Enhanced IL-12 transgene expression improves oncolytic viroimmunotherapy.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with unacceptably low cure rates occurring often in patients with neurofibromatosis 1 defects. To investigate oncolytic Herpes Simplex Virus (oHSV) as an immunotherapeutic approach, we compared viral replication, functional activity, and immune response between unarmed and interleukin 12 (IL-12)-armed oncolytic viruses in virus-permissive (B109) and -resistant (67C-4) murine MPNSTs. This study compared two attenuated IL-12-oHSVs with γ134.5 gene deletions (Δγ134.5) and the same transgene expression cassette. The primary difference in the IL-12-oHSVs was in their ability to counter the translational arrest response in infected cells. Unlike M002 (Δγ134.5, mIL-12), C002 (Δγ134.5, mIL-12, IRS1) expresses an HCMV IRS1 gene and evades dsRNA activated translational arrest in infected cells. Our results show that oHSV replication and gene expression results in vitro were not predictive of oHSV direct oncolytic activity in vivo. Tumors that supported viral replication in cell culture studies resisted viral replication by both oHSVs and restricted M002 transgene expression in vivo. Furthermore, two IL-12-oHSVs with equivalent transcriptional activity differed in IL-12 protein production in vivo, and the differences in IL-12 protein levels were reflected in immune infiltrate activity changes as well as tumor growth suppression differences between the IL-12-oHSVs. C002-treated tumors exhibited sustained IL-12 production with improved dendritic cells, monocyte-macrophage activity (MHCII, CD80/CD86 upregulation) and a polyfunctional Th1-cell response in the tumor infiltrates. These results suggest that transgene protein production differences between oHSVs in vivo, in addition to replication differences, can impact OV-therapeutic activity.
cell therapies
2026-05-06 | Immediate Nerve and Tendon Transfers After Wide Resection of a Radial Nerve Malignant Peripheral Nerve Sheath Tumor: A Case Report and Surgical Technique.
The authors have reported on immediate nerve and tendon transfers postresection of a radial nerve-based malignant peripheral nerve sheath tumor in a 15-year-old female with neurofibromatosis. The median nerve branch to flexor carpi radialis was transferred to the posterior interosseous nerve, the median nerve branch to flexor digitorum superficialis was transferred to the nerve to extensor carpi radialis brevis, and the pronator teres tendon was transferred to the extensor carpi radialis brevis tendon, with 3-year outcomes reported. Tumor excision, tendon, and nerve transfer yielded negative margins and remission. Functional wrist/finger extension appeared at 6 months and increased until 3 years of follow-up.
2025-09-02 | Evaluating CAR-T cells from neurofibromatosis type 1 (NF1) patients for targeting AXL in malignant peripheral nerve sheath tumors associated with NF1.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by neurofibromas, with 5-13% of patients risk developing malignant peripheral nerve sheath tumors (MPNST). Current treatments for MPNST are largely ineffective. AXL, overexpressed in MPNST, is a potential target for Chimeric Antigen Receptor T (CAR-T) cell therapy. This study evaluates the immunophenotypes, efficacy, and safety of NF1-derived AXL-CAR-T cells in treating MPNST. AXL-CAR-T cells, containing an anti-AXL single-chain variable fragment, were derived from NF1 patients (n = 27) and healthy donors (n = 15). Immunophenotypes were characterized using CCR7, CD45RA, CD4, and CD8 markers. The cytotoxicity of CAR-T cells was tested in vitro against MPNST cells, and efficacy and safety were evaluated in an MPNST xenograft mouse model. Multiplex immunoassays and ELISA measured cytokines and granzyme b release. AXL-CAR-T cells from both NF1 patients and healthy donors had a similar partition in stem cell-like memory T cell composition and comparable ex vivo expansion. AXL-CAR-T cells from both groups effectively lysed MPNST cells in vitro. In vivo, tumor volumes in xenograft mice were significantly reduced with no on-target off-tumor toxicity. NF1 patient-derived AXL-CAR-T cells demonstrated similar quality and efficacy to those from healthy donors, supporting their potential autologous therapy for MPNST.
2025-07-19 | New models for MPNST: establishment and comprehensive characterization of two tumor cell lines.
Malignant peripheral nerve sheath tumors (MPNSTs) are rare, invasive, and aggressive soft tissue sarcomas arising from peripheral nerves. They may occur sporadically or in association with Neurofibromatosis type 1 (NF1), in which they are the leading cause of mortality. Currently, there are no effective therapies other than surgery. Therefore, tumor-derived cell lines are essential for testing new therapeutic strategies, especially when used in parallel with in vivo models. In this study, we present two new MPNST cell lines and two patient-derived orthotopic xenograft (PDOX) models from a sporadic (SP-10) and an NF1-related (NF1-18B) MPNST patient to increase the number of available preclinical models for in vitro and in vivo drug testing. The cell lines were isolated and extensively characterized genetically (tumor suppressor gene mutation status, DNA content), phenotypically (cell morphology, marker expression), and functionally (proliferation rate, colony formation capacity, migration rate, tumorigenic ability). We validated the models by comparing the genomic (copy number variation profile) and histological characteristics of the cell lines and PDOX tumors with their corresponding patient tumors. The new cell lines and PDOXs tumors exhibited similar genomic copy number variation profiles, histological patterns, and marker expressions as the patient tumors, validating them as faithful models. Interestingly, the NF1-18B cell model presented two cell subpopulations with different ploidy states (one < 3n and the other 4n) and functional features in vitro. NF1-18B 4n, along with SP-10 cell lines, exhibited in vitro functional hallmarks of MPNSTs, including high proliferation and migration rates and colony forming ability. However, only the SP-10 model exhibited aggressive tumorigenicity in athymic mice. In contrast, the NF1-18B < 3n showed a low migration rate and did not form colonies or aggregates in vitro. The newly established MPNST cell lines, along with their corresponding PDOX models, serve as valuable tools for both in vitro and in vivo testing of novel therapeutic agents. Notably, the SP-10 cell line model represents one of the few documented cases isolated from a genuine "classic" MPNST.
2025-04-26 | Pedicled Vascularized Common Peroneal Nerve Graft in Sciatic Nerve Reconstruction With Involvement of Inner Pelvic Lumbar and Sacral Nerve Roots: A Case Report and Literature Review.
Long segment losses exceeding 10 cm in the sciatic nerve are challenging in both the reconstructive techniques and optimizing sensory and motor function recovery. This case report and literature review describes our experience of using a pedicled vascularized common peroneal nerve graft to repair a 14-cm sciatic nerve defect, involving L4, L5, and S1 nerve roots. Additionally, we conducted a literature review of various types of nerve autografts for large sciatic nerve defects, summarizing their characteristics and outcomes to aid clinicians in decision-making and expected results in different scenarios. The patient, a 23-year-old female diagnosed with neurofibromatosis type I, underwent R0 tumor resection of the proximal left sciatic nerve due to a malignant peripheral nerve sheath tumor. She received an ipsilateral pedicled vascularized common peroneal nerve graft. The reconstruction included the L4, L5, and S1 nerve roots beyond the greater sciatic foramen into the inner pelvis. The patient's postoperative course was uneventful. At the 26-month follow-up, she showed MRC grade 4/5 strength in hamstrings with 90°knee flexion and a steady gait pattern. At the 32-month follow-up, she could ambulate very well with an ankle-foot orthosis. The outcomes support the use of a pedicled vascularized common peroneal nerve graft in a single-staged surgery to restore motor function for large sciatic nerve defects. Our literature review revealed that in cases where sural nerves are insufficient or injured for sciatic nerve reconstruction, the common peroneal nerve is a viable alternative to help patients regain functional independence.
2024-04-08 | Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient-derived orthotopic xenografts, cell lines and tumor entities.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heterogeneity could be partly responsible for the observed disparity in treatment response due to the inherent diversity of the preclinical models used. For several years, our group has been generating a large patient-derived orthotopic xenograft (PDOX) MPNST platform for identifying new precision medicine treatments. Herein, we describe the expansion of this platform using six primary tumors clinically diagnosed as MPNSTs, from which we obtained six additional PDOX mouse models and three cell lines, thus generating three pairs of in vitro-in vivo models. We extensively characterized these tumors and derived preclinical models, including genomic, epigenomic, and histological analyses. Tumors were reclassified after these analyses: three remained as MPNSTs (two being classic MPNSTs), one was a melanoma, another was a neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasm, and, finally, the last was an unclassifiable tumor bearing neurofibromin-2 (NF2) inactivation, a neuroblastoma RAS viral oncogene homolog (NRAS) oncogenic mutation, and a SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (SMARCA4) heterozygous truncated variant. New cell lines and PDOXs faithfully recapitulated histology, marker expression, and genomic characteristics of the primary tumors. The diversity in tumor identity and their specific associated genomic alterations impacted treatment responses obtained when we used the new cell lines for testing compounds against known altered pathways in MPNSTs. In summary, we present here an extension of our MPNST precision medicine platform, with new PDOXs and cell lines, including tumor entities confounded as MPNSTs in a real clinical scenario. This platform may constitute a useful tool for obtaining correct preclinical information to guide MPNST clinical trials.
antibodies
2026-09-21 | A Reproducible Transcriptomic Program of Neurofibroma-to-Malignant Peripheral Nerve Sheath Tumor Transformation.
Malignant peripheral nerve sheath tumor (MPNST) carries the highest excess mortality of the cancers associated with neurofibromatosis Type 1, and usually arises from a neurofibroma. We asked whether the transcriptomic differences that distinguish MPNST from neurofibroma reproduce across independent cohorts, and whether a compact score derived from them transports between platforms. We meta-analyzed five public discovery cohorts of primary nerve-sheath tissue (113 MPNST, 79 neurofibromas; 3 platforms) and held out a sixth, independently generated cohort. Neurofibroma and MPNST tissue differed at 1489 genes in two opposing themes: up-regulated mitotic machinery (TOP2A, EZH2, AURKA) and loss of Schwann-cell identity (the transcription factors SOX10 and EGR2, and the myelin genes PMP2 and MPZ). These differences were reproducible. Among the significant genes assayed in all five cohorts, almost all changed in the same direction in everyone, and 93.3% of those detectable in the held-out cohort agreed in direction. Leave-one-cohort-out re-derivation of the pipeline gave a mean AUC of 0.90 across five folds (per-fold 0.84 to 0.97). CD276 (B7-H3) was selectively up-regulated, whereas CD274 and PDCD1LG2 were not. The myelin marker PMP2, a readout chosen retrospectively after the held-out results were known, separated MPNST from neurofibroma in that cohort but left atypical and conventional neurofibromas unseparated (AUC 0.67, p = 0.10). A program score derived without the discovery cohort carrying survival data was associated with shorter survival there, an exploratory single-cohort association. The composition of a compact score varied with platform and preprocessing, so no fixed single-sample classifier is warranted.
2026-09-18 | Pediatric Superficial Malignant Perineurioma/Perineuriomatous Malignant Peripheral Nerve Sheath Tumor of the Groin With NF1 Loss: A Case Report and Focused Review of the Literature.
Malignant perineurioma, also referred to as perineuriomatous malignant peripheral nerve sheath tumor (MPNST), is an exceptionally rare neoplasm with limited clinicopathologic characterization, particularly in children. We report a 12-year-old boy with a 3.0-cm superficial right groin lesion. Histopathologic examination showed a spindle cell neoplasm with fascicular-to-swirling architecture in myxoid to collagenous stroma, moderate cytologic atypia and nuclear variability, mitotic activity, focal necrosis, and admixed inflammation. Epithelial membrane antigen, GLUT1, and claudin-1 positivity supported perineurial differentiation, while a broad negative immunohistochemical panel helped exclude potential mimics. Tumor-only sequencing demonstrated 17q loss with focal homozygous NF1 deletion, a BRCA2 frameshift, and low tumor mutational burden (3.4 mutations/Mb); RNA sequencing identified no pathogenic gene fusion. These molecular findings were interpreted as adjunctive rather than independently diagnostic. The tumor extended to the inked specimen edge, and subsequent management and follow-up information was unavailable. To our knowledge, this is the first reported superficial cutaneous malignant perineurioma/perineuriomatous MPNST in a pediatric patient.
2026-09-01 | Real-world experience with ipilimumab in combination with nivolumab in advanced sarcoma: a retrospective analysis including ultra-rare sarcomas.
Patients with locally advanced or metastatic sarcoma have a poor prognosis and limited efficacious treatment options. Phase 2 trials have demonstrated efficacy for the combination of ipilimumab and nivolumab in select sarcoma histologies, but real-world data is limited. In this single-institution retrospective analysis, patients with metastatic or unresectable sarcoma treated with the combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab were assessed for response by iRECIST criteria and were correlated with clinical outcomes. The Kaplan-Meier method was used for survival analysis. From 2019 to 2024, 90 patients with advanced sarcoma were treated with combination ICI and were evaluable for outcomes. The observed objective response rate (ORR) was 16.7% with clinical benefit rate (CBR) of 30%. The best response was partial response (PR) in 14.4%, stable disease (SD) in 23.3%, and progressive disease (PD) in 62.2%. Median overall survival (OS) (95% confidence interval [CI] 14.4-NE months) and median progression-free survival (mPFS) (95% CI, 9.6-NE months) were not reached for patients achieving an objective response. OS was superior in patients who experienced immune-related adverse events (irAEs). Both mPFS and median overall survival were superior in patients with thyroid irAEs. Highest ORR were seen in angiosarcoma, malignant peripheral nerve sheath tumor, leiomyosarcoma, undifferentiated pleomorphic sarcoma, and chondrosarcoma. Real-world analysis of combination ICI in a large cohort of heavily pretreated patients with advanced sarcomas demonstrates clinical benefit in a meaningful number of patients, including historically unresponsive histologies, though predictive factors remain elusive. The development of irAEs, specifically thyroid dysfunction, was associated with improved survival. Sustained responses were observed in patients who achieved an objective response.
2026-08-02 | Intratumoural plasma cells mediate a pro-inflammatory response to kinase inhibition and successful immune checkpoint blockade therapy in malignant peripheral nerve sheath tumours.
The role of intratumoural plasma cells in immune checkpoint blockade (ICB) therapy has never been tested although their presence is linked with improved response and survival in people with cancer. Malignant peripheral nerve sheath tumours (MPNSTs) are deadly sarcomas with minimal responsiveness to ICB therapies. Strikingly, drugs inhibiting cyclin-dependent kinases 4/6 (CDK4/6) and MEK sensitise de novo MPNSTs to immunotherapy targeting programmed death-ligand 1 (PD-L1), which correlates with increased intratumoural plasma cells. Here, we tested if plasma cells mediate MPNST response to anti-PD-L1 therapy and how they modulate tumour immune responsiveness to CDK4/6-MEK inhibition. Anti-tumour activity of PD-L1 inhibition, with or without CDK4/6-MEK inhibition, was measured in de novo MPNSTs within wild-type versus plasma cell-deficient mice. Plasma cell-dependent effects of CDK4/6-MEK inhibition on priming the MPNST immune environment were determined by single cell transcriptomics and immune cell analyses. Plasma cell-deficient MPNSTs failed to respond to anti-PD-L1 monotherapy and were no longer sensitised by CDK4/6-MEK inhibition to immunotherapy. Following kinase inhibitor treatment, plasma cells were necessary for a pro-inflammatory response marked by increased tumour infiltration and activation of natural killer (NK) and CD8+ T cells, major histocompatibility class I antigen presentation, and decreased M2 macrophages. By comparison, elevated CD4+ T cell and B cell infiltration dominated the plasma cell knockout phenotype. Plasma cells favourably remodel the tumour immune environment for anti-tumour immunity and are critical for successful ICB therapy in MPNSTs. These findings may inform ICB treatment strategies and patient stratification for therapy of many tumour types. This research was supported by University of Iowa Sarcoma Research Program awards, the Gilbert Family Foundation, and NIH grants T34-GM141143, T32-GM067795, F31-CA281312, P30-CA086862, and R01-NS119322.
2026-06-30 | Primary colonic malignant peripheral nerve sheath tumor with biphasic morphology: A case report
BACKGROUNDMalignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive soft tissue sarcoma, in which primary colonic involvement is exceptionally uncommon.Previously reported colonic cases have mostly shown a conventional spindle-cell morphology, while cases with unusual histologic patterns remain poorly characterized. CASE SUMMARYIn the reported case, a 75-year-old man presented with intermittent right upper abdominal pain and abdominal distension.He underwent contrast-enhanced computed tomography, which revealed a large invasive mass extending from the right subphrenic region to the gallbladder fossa, with indistinct borders from the adjacent liver, duodenum, and pancreatic head.Exploratory laparotomy and right hemicolectomy were performed.Histologically, the tumor displayed a biphasic pattern composed of approximately a 30% spindle-cell component and 70% small round-cell component.The spindle-cell areas consisted of intersecting fascicles of atypical spindle cells with hyperchromatic nuclei and brisk mitotic activity, while the small round-cell areas were composed of densely packed primitive-looking cells with scant cytoplasm and hyperchromatic nuclei.Tumor necrosis was also observed.Immunohistochemically, S-100 showed patchy positivity in approximately 40% of tumor cells, while cytokeratins, smooth muscle markers, melanocytic markers, and Ewing sarcoma-related markers were negative.The Ki-67 Labeling index was very high, at approximately 90%, and a complete loss of H3K27me3 was observed in all the tumor cell nuclei.Based on the morphologic features, immunophenotype, and exclusion of major differential diagnoses, the lesion was diagnosed as a primary sporadic high-grade MPNST of the colon.Despite complete resection of the tumor with negative margins, the patient rapidly developed massive pleural and peritoneal effusions after surgery, which then progressed to respiratory failure, and he ultimately died on postoperative day 13. 4 / 36 CONCLUSION Primary colonic MPNST may present with an atypical biphasic spindle and small round cell morphology, creating a potential diagnostic overlap with other high-grade mesenchymal malignancies of the colon.In challenging cases, a consideration of the H3K27me3 status may provide important ancillary diagnostic support.Even after complete resection, tumors with high-risk pathologic features may follow an extremely aggressive clinical course, underscoring the need for early recognition, accurate pathologic diagnosis, close postoperative surveillance, and multidisciplinary management.
other
2025-05-15 | Supplementary Figure S6 from DLK1 Distinguishes Subsets of NF1-Associated Malignant Peripheral Nerve Sheath Tumors with Divergent Molecular Signatures
<p>In vitro overexpression of DLK1 in human PNF and MPNST cell lines</p>
2024-11-01 | BIOM-37. EXPLORING L-TYPE AMINO ACID TRANSPORTER 1 (LAT1) AS A DIAGNOSTIC MARKER AND THERAPEUTIC TARGET IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNST)
Abstract OBJECTIVES Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that frequently arise from benign plexiform neurofibromas (PN). Approximately half of MPNST are associated with Neurofibromatosis type 1 (NF1). Despite partial elucidation of the molecular mechanisms underlying MPNST, diagnosis remains challenging, and prognosis is poor. Previously, we found that MPNST cells have elevated βIII-spectrin, a cytoskeletal protein involved in cell morphology and regulation of transporters, including L-type Amino Acid Transporter 1 (LAT1). LAT1 facilitates transport of large neutral amino acids and is upregulated in other cancer types. Our objective is to investigate LAT1 as a diagnostic marker and therapeutic target for MPNST. METHODS Gene and protein expression were determined by qPCR and WES protein analysis, respectively. The effect of shRNA knockdown of LAT1 in MPNST cells was assessed using IncuCyte proliferation assays as well as multiple mouse models. Tumor uptake of [18F] FDOPA, primarily transported by LAT1, in MPNST PDX tumors was assessed using PET/CT imaging. RESULTS LAT1 was expressed in MPNST (n=14) vs. benign PN tissues (n=6). Additionally, in human and murine MPNST cells, shRNA-mediated knockdown of LAT1 suppressed proliferation of MPNST cells in vitro and tumor growth in vivo. In a subcutaneous tumor growth model, intratumor injection of shLAT1 lentivirus reduced tumor volume to approximately 50% of control. Furthermore, uptake of [18F] FDOPA by LAT1 in MPNST PDX tumors was detected by PET/CT imaging. WU-356 PDX tissues exhibited higher LAT1 expression as well as increased uptake of [18F] FDOPA in tumors. Conversely, PET imaging showed significantly lower uptake of [18F] FDOPA in LAT1 knockdown tumors (p<0.05). CONCLUSIONS These results suggest that LAT1 promotes the growth and survival of MPNST cells. In addition, these findings demonstrate the potential use of LAT1 and the radiotracer [18F] FDOPA as a diagnostic biomarker in the management of MPNST.
2024-07-12 | The Use of Hexokinase 2-Displacing Peptides as an Anti-Neoplastic Approach for Malignant Peripheral Nerve Sheath Tumors.
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.
2024-01-11 | Deciphering the Immune Microenvironment of NF1-associated Peripheral Nerve Sheath Tumors: Identifying Early Biomarkers of Disease Progression and Malignant Transformation
Background/Objective:Neurofibromatosis type 1 (NF1) is a multisystem disorder that affects ~1/3000 newborns. Plexiform neurofibromas (PN) are present in about half of cases and can transform (lifetime risk of 8-13%) into malignant peripheral nerve sheath tumor (MPNST), a highly aggressive and metastatic sarcoma with poor survival. Unfortunately, there are currently no reliable biomarkers to identify PN at risk of undergoing malignant transformation. Our research has revealed that a subset of benign-appearing and atypical PN exhibit deregulated immune surveillance and T-cell infiltration that precede malignant transformation. In this study, we are analyzing tumor microenvironment and immune landscape in NF1-related tissue specimens to identify biomarkers of disease progression. To power these studies, this project focused on constructing a dataset of NF1-related samples to be analyzed. Methods:701 patients were identified via Cerner billing codes and pathology archives. De-identified clinical data, including presenting symptoms, relevant clinical history, pathology diagnoses, disease features, prior chemotherapeutics/radiation, prior gene profiling, and imaging features were collected. Results: We selected 86 patients with a total of 175 samples. 81% of patients had a clinical diagnosis of NF1, and 6% had a history of MPNST. Out of the 175 samples, 54 were in the head and neck, 42 in the thorax, 28 in the lower extremity, 27 in the upper extremity, 26 in the pelvis/abdomen, and 15 in the paraspinal region. The leading causes of procedures were pain (41%), growth (40%), and concern for malignancy (27%). The most common tissue diagnoses were neurofibroma (51.4%), PN (20%), and undefined-grade MPNST (11%). Out of the 46 MPNSTs, 30 were primary tumors, 4 metastases, and 12 local recurrences. Conclusion and Potential Impact:The results of this study will provide valuable insights to inform preclinical models of NF1-tumorigenesis to validate these findings and identify novel treatment approaches for individuals affected by these rare but devastating tumors.
2023-03-28 | Delineating the tumour-regulatory roles of EYA4.
Eyes absent homolog 4 (EYA4) is a protein that regulates many vital cellular processes and organogenesis pathways. It possesses phosphatase, hydrolase, and transcriptional activation functions. Mutations in the Eya4 gene can cause sensorineural hearing loss and heart disease. In most non-nervous system cancers such as those of the gastrointestinal tract (GIT), hematological and respiratory systems, EYA4 acts as a putative tumor suppressor. However, in nervous system tumors such as glioma, astrocytoma, and malignant peripheral nerve sheath tumor (MPNST), it plays a putative tumor-promoting role. EYA4 interacts with various signaling proteins of the PI3K/AKT, JNK/cJUN, Wnt/GSK-3β, and cell cycle pathways to exert its tumor-promoting or tumor-suppressing effect. The tissue expression level and methylation profiles of Eya4 can help predict the prognosis and anti-cancer treatment response among cancer patients. Targeting and altering Eya4 expression and activity could be a potential therapeutic strategy to suppress carcinogenesis. In conclusion, EYA4 may have both putative tumor-promoting and tumor-suppressing roles in different human cancers and has the potential to serve as a prognostic biomarker and therapeutic agent in various cancer types.
small molecules
2026-09-18 | PRC2 loss in MPNST is accompanied by SWI/SNF complex rewiring and sensitization to SMARCA2/4 and BET inhibition in vivo.
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas of peripheral nerve sheath that frequently arise in patients with neurofibromatosis type 1 (NF1) and currently have no approved targeted treatment. Loss of Polycomb Repressive Complex 2 (PRC2) activity, through inactivating mutations in SUZ12 or EED, occurs in 50 to 80% of NF1-associated MPNSTs, leads to depletion of H3K27me3 in cells, global epigenetic dysregulation, and serves as an indicator of poor clinical outcomes. SWI/SNF (BAF) complexes are ATPase-driven chromatin remodelers essential for orderly transcriptional activity in cells. Because PRC2 and SWI/SNF enforce functionally antagonistic effects on chromatin, we hypothesized that PRC2-deficient MPNSTs undergo alterations in the SWI/SNF complex that create a therapeutic vulnerability to SWI/SNF inhibition. We performed integrated proteogenomic profiling of patient-derived MPNST cell lines stratified by PRC2 status: Loss of Function (LoF) or Wild Type (WT). We found that PRC2 loss in MPNST was associated with broad reduction in global SWI/SNF protein abundance, recurrent enrichment of SMARCD3 in SMARCA4-containing complexes, and context-dependent enrichment of DPF3 and PBAF-specific subunits. ChIP-seq analyses showed redistribution of cBAF and PBAF chromatin occupancy in PRC2 LoF models followed by concordant increases in H3K27ac signal and gene expression. Cell fitness assays revealed that the SWI/SNF ATPase inhibitor, FHD-286, reduced cell viability in PRC2 LoF MPNST lines at low nanomolar concentrations and disrupted the colony forming ability, while PRC2 WT cell lines were less sensitive to treatment. Finally, evaluating the efficacy of FHD-286 alone, and in combination with I-BET-762, in an isogenic PRC2 loss murine allograft MPNST model, we observed enhanced efficacy of the combination regimen compared to either single agent in the Suz12 KO arm, while in the Suz12 WT arm, the combo was outperformed by I-BET-762 alone. Together, our findings indicate that PRC2 loss in MPNST is accompanied by selective subunit remodeling and genomic redistribution of SWI/SNF complexes and support SWI/SNF ATPase inhibition, alone and in combination with BET inhibition, as an attractive therapeutic strategy for PRC2-deficient MPNSTs.
2026-09-13 | 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.
2026-09-11 | RBPMS::NTRK3-rearranged sacral malignant spindle cell tumor in neurofibromatosis diagnosed by RNA sequencing: a case report and literature review.
Malignant spindle cell tumors arising in patients with neurofibromatosis are diagnostically challenging because malignant peripheral nerve sheath tumor (MPNST) and emerging NTRK-rearranged mesenchymal neoplasms may show overlapping clinical, histological, and immunophenotypic features. We report a 31-year-old man with a more than 20-year history of neurofibromatosis who presented with progressive lumbosacral pain and left lower-limb numbness. Imaging revealed a large cystic-solid sacral mass involving the S1-S2 region and extending through the sacral foramina into the pelvis. Core needle biopsy showed an intermediate-grade malignant spindle cell tumor with partial CD34 expression, strong pan-TRK positivity, increased p53 expression, and a Ki-67 labeling index up to 50% in hotspot areas. NTRK1 break-apart fluorescence in situ hybridization (FISH) was negative; however, RNA-based next-generation sequencing identified an RBPMS::NTRK3 fusion, establishing a molecularly confirmed NTRK3-rearranged spindle cell neoplasm and explaining the pan-TRK positivity as a true-positive result. The negative NTRK1 FISH reflected involvement of NTRK3 rather than NTRK1, illustrating that single-gene FISH cannot exclude an NTRK fusion. Given the large local tumor burden, neurological symptoms, high surgical morbidity, and the confirmed actionable fusion, the patient received molecularly guided entrectinib combined with palliative radiotherapy, with marked pain relief, neurological improvement, and radiological tumor shrinkage; at the most recent follow-up, approximately 7 months after starting entrectinib, he remained without evidence of disease progression. This case underscores that pan-TRK positivity should prompt confirmatory RNA-based sequencing rather than reliance on single-gene FISH; that actionable NTRK fusions may occur in the neurofibromatosis setting, where MPNST is the principal differential; and that molecularly informed multimodal therapy can benefit anatomically complex tumors, although response attribution requires caution when targeted therapy and radiotherapy are combined.
2026-09-09 | Combination of EZH2 and MEK inhibitors as an effective therapy for neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.
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. 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. 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. 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.
2026-09-01 | Ornithine decarboxylase levels in peripheral nerve sheath tumors from NF1 patients.
The study was conducted to determine the level of ornithine decarboxylase (ODC) activity in several types of peripheral nerve sheath tumors to assess ODC as a potential target for alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. A formalin-fixed paraffin-embedded peripheral nerve sheath tumor tissue microarray was developed in the Department of Anatomic Pathology, MD Anderson Cancer Center. ODC levels were measured using immunofluorescence with a polyclonal antibody to ODC and Alexa-Fluor 647 goat anti-rabbit IgG using previously validated and established methodology. Nuclear and cytoplasmic ODC levels were assessed to determine surrogate ODC activity based on immunofluorescence from 11 patients with a spectrum of nerve sheath tumors, including malignant peripheral nerve sheath tumors (MPNSTs), plexiform neurofibroma, WHO Grade 1 (NF), atypical neurofibroma neoplasm of uncertain biologic potential (ANNUBP), and schwannoma. ODC activity was less than 5 nmol/30 min/min/ug ODC protein in many MPNST, NF, and schwannomas, but higher than 10 nmol/min/ug protein in ANNUBP tumors and one NF tumor. Nuclear ODC activity varied across peripheral nerve sheath tumors, with relatively low to moderate levels observed in MPNSTs and higher levels in ANNUBP tumors within the small cohort studied. Since DFMO, an irreversible ODC inhibitor, is more effective in slow-growing grade 2 and 3 gliomas with low ODC levels than in higher malignancy grade 4 glioma with high ODC activity, it is reasonable to assume that MPNSTs and neurofibromas, WHO grade, with relatively low to moderate levels of ODC activity may be suitable candidates for DFMO therapy. However, larger studies are needed to validate ODC activity as a predictive biomarker and to determine the therapeutic efficacy of DFMO in peripheral nerve sheath tumors.
gene therapies
2025-11-26 | Challenges and Progress for Treatment of Malignant Peripheral Nerve Sheath Tumors in the Context of Recent Successes for Sarcoma Therapy
Malignant peripheral nerve sheath tumors (MPNSTs) are one of the most difficult sarcomas to treat. Due to the rarity of MPNSTs, many of the therapeutic approaches used are from treatment guidelines for soft tissue sarcoma. Besides surgery, little success has been achieved using these therapies. Traditional chemotherapy and radiation therapy regimens designed to treat sarcoma have unclear efficacy when used to treat MPNSTs. Targeted therapeutics that succeeded in other sarcomas failed to produce positive results in MPNSTs. Moreover, investigational agents that have shown efficacy in preclinical models have produced disappointing outcomes in clinical trials. While therapeutic options for patients with MPNST have remained relatively stagnant, dramatic improvements in therapeutic outcomes of other rare sarcomas have been made. This difference in success is likely caused by the complex heterogeneity of MPNSTs that hinders drug development, although many MPNSTs are associated with neurofibromatosis type 1 (NF1), a genetic disorder resulting from mutations in the NF1 gene that encodes the negative RAS regulator neurofibromin. The development of new agents for MPNST treatment has shifted away from solely targeting RAS pathway gene products to stimulating the immune system and manipulating other MPNST driver mutations such as CDKN2A/B, SUZ12, EED, and TP53. This review presents recent advances in the treatment of sarcomas and the future of drug development targeting MPNSTs.
2025-11-26 | Neurofibromatosis Type 1: Genetic Mechanisms and Advances in Therapeutic Innovation
Mutations in the NF1 gene cause Neurofibromatosis Type 1 (NF1), one of the most common genetic disorders. This gene encodes neurofibromin, a member of the GTPase-activating protein (GAP) family that functions as a negative regulator of RAS signaling. Loss of NF1 function leads to persistent RAS activation and promotes tumor growth. The clinical manifestations of NF1 mainly include pigmentary changes, benign and malignant peripheral nerve sheath tumors, as well as gliomas affecting the central nervous system. Currently, MEK inhibition is the only approved therapy and is primarily effective in controlling plexiform neurofibromas (pNFs). However, more comprehensive treatments are needed to address the full spectrum of NF1 manifestations and malignant transformation. Novel therapeutic strategies, including AAV-based gene therapy aimed at restoring NF1 function, oncolytic herpes simplex virus (oHSV) therapy targeting RAS-dysregulated tumor cells, and chimeric antigen receptor T cell (CAR-T) therapy targeting NF1-associated tumors, are under active investigation. In this review, we explore the genetic mechanisms underlying NF1 and highlight recent advances in therapeutic development with a special focus on AAV-based gene therapies alongside other approaches with recent clinical and translational advancements.
2025-09-30 | Development of an adeno-associated virus vector for gene replacement therapy of NF1-related tumors.
Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome caused by alterations in NF1 gene that lead to tumor growth throughout the nervous system, which can cause morbidity and mortality, and transform to malignancy. NF1 gene replacement therapy, though promising, is hindered by NF1 gene's large size and delivery challenges. We introduced a membrane-targeted, truncated neurofibromin comprising the GAP-related domain (GRD) fused to the KRAS4B C-terminal domain, which effectively inhibits the RAS signaling pathway and restores Schwann cell differentiation in an NF1 iPSC-derived model. For systemic application, we engineered an adeno-associated virus (AAV) vector using in vivo capsid evolution through sequential DNA shuffling and peptide library screening in a NF1 xenograft mouse model. This tailored vector, AAV-NF, exhibits greatly reduced liver uptake, enhanced tumor targeting across various NF1-related MPNST, neurofibromas and glioma models, and therapeutic efficacy in xenografts of MPNST. This study not only advances a viable AAV vector for NF1 treatment but also outlines a replicable strategy for vector and payload development in other monogenic and tumor-associated disease manifestations.
2024-07-09 | Corrigendum: Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors
Corrigendum: Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors
2024-06-19 | Enhanced IL-12 transgene expression improves oncolytic viroimmunotherapy.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with unacceptably low cure rates occurring often in patients with neurofibromatosis 1 defects. To investigate oncolytic Herpes Simplex Virus (oHSV) as an immunotherapeutic approach, we compared viral replication, functional activity, and immune response between unarmed and interleukin 12 (IL-12)-armed oncolytic viruses in virus-permissive (B109) and -resistant (67C-4) murine MPNSTs. This study compared two attenuated IL-12-oHSVs with γ134.5 gene deletions (Δγ134.5) and the same transgene expression cassette. The primary difference in the IL-12-oHSVs was in their ability to counter the translational arrest response in infected cells. Unlike M002 (Δγ134.5, mIL-12), C002 (Δγ134.5, mIL-12, IRS1) expresses an HCMV IRS1 gene and evades dsRNA activated translational arrest in infected cells. Our results show that oHSV replication and gene expression results in vitro were not predictive of oHSV direct oncolytic activity in vivo. Tumors that supported viral replication in cell culture studies resisted viral replication by both oHSVs and restricted M002 transgene expression in vivo. Furthermore, two IL-12-oHSVs with equivalent transcriptional activity differed in IL-12 protein production in vivo, and the differences in IL-12 protein levels were reflected in immune infiltrate activity changes as well as tumor growth suppression differences between the IL-12-oHSVs. C002-treated tumors exhibited sustained IL-12 production with improved dendritic cells, monocyte-macrophage activity (MHCII, CD80/CD86 upregulation) and a polyfunctional Th1-cell response in the tumor infiltrates. These results suggest that transgene protein production differences between oHSVs in vivo, in addition to replication differences, can impact OV-therapeutic activity.
cell therapies
2026-05-06 | Immediate Nerve and Tendon Transfers After Wide Resection of a Radial Nerve Malignant Peripheral Nerve Sheath Tumor: A Case Report and Surgical Technique.
The authors have reported on immediate nerve and tendon transfers postresection of a radial nerve-based malignant peripheral nerve sheath tumor in a 15-year-old female with neurofibromatosis. The median nerve branch to flexor carpi radialis was transferred to the posterior interosseous nerve, the median nerve branch to flexor digitorum superficialis was transferred to the nerve to extensor carpi radialis brevis, and the pronator teres tendon was transferred to the extensor carpi radialis brevis tendon, with 3-year outcomes reported. Tumor excision, tendon, and nerve transfer yielded negative margins and remission. Functional wrist/finger extension appeared at 6 months and increased until 3 years of follow-up.
2025-09-02 | Evaluating CAR-T cells from neurofibromatosis type 1 (NF1) patients for targeting AXL in malignant peripheral nerve sheath tumors associated with NF1.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by neurofibromas, with 5-13% of patients risk developing malignant peripheral nerve sheath tumors (MPNST). Current treatments for MPNST are largely ineffective. AXL, overexpressed in MPNST, is a potential target for Chimeric Antigen Receptor T (CAR-T) cell therapy. This study evaluates the immunophenotypes, efficacy, and safety of NF1-derived AXL-CAR-T cells in treating MPNST. AXL-CAR-T cells, containing an anti-AXL single-chain variable fragment, were derived from NF1 patients (n = 27) and healthy donors (n = 15). Immunophenotypes were characterized using CCR7, CD45RA, CD4, and CD8 markers. The cytotoxicity of CAR-T cells was tested in vitro against MPNST cells, and efficacy and safety were evaluated in an MPNST xenograft mouse model. Multiplex immunoassays and ELISA measured cytokines and granzyme b release. AXL-CAR-T cells from both NF1 patients and healthy donors had a similar partition in stem cell-like memory T cell composition and comparable ex vivo expansion. AXL-CAR-T cells from both groups effectively lysed MPNST cells in vitro. In vivo, tumor volumes in xenograft mice were significantly reduced with no on-target off-tumor toxicity. NF1 patient-derived AXL-CAR-T cells demonstrated similar quality and efficacy to those from healthy donors, supporting their potential autologous therapy for MPNST.
2025-07-19 | New models for MPNST: establishment and comprehensive characterization of two tumor cell lines.
Malignant peripheral nerve sheath tumors (MPNSTs) are rare, invasive, and aggressive soft tissue sarcomas arising from peripheral nerves. They may occur sporadically or in association with Neurofibromatosis type 1 (NF1), in which they are the leading cause of mortality. Currently, there are no effective therapies other than surgery. Therefore, tumor-derived cell lines are essential for testing new therapeutic strategies, especially when used in parallel with in vivo models. In this study, we present two new MPNST cell lines and two patient-derived orthotopic xenograft (PDOX) models from a sporadic (SP-10) and an NF1-related (NF1-18B) MPNST patient to increase the number of available preclinical models for in vitro and in vivo drug testing. The cell lines were isolated and extensively characterized genetically (tumor suppressor gene mutation status, DNA content), phenotypically (cell morphology, marker expression), and functionally (proliferation rate, colony formation capacity, migration rate, tumorigenic ability). We validated the models by comparing the genomic (copy number variation profile) and histological characteristics of the cell lines and PDOX tumors with their corresponding patient tumors. The new cell lines and PDOXs tumors exhibited similar genomic copy number variation profiles, histological patterns, and marker expressions as the patient tumors, validating them as faithful models. Interestingly, the NF1-18B cell model presented two cell subpopulations with different ploidy states (one < 3n and the other 4n) and functional features in vitro. NF1-18B 4n, along with SP-10 cell lines, exhibited in vitro functional hallmarks of MPNSTs, including high proliferation and migration rates and colony forming ability. However, only the SP-10 model exhibited aggressive tumorigenicity in athymic mice. In contrast, the NF1-18B < 3n showed a low migration rate and did not form colonies or aggregates in vitro. The newly established MPNST cell lines, along with their corresponding PDOX models, serve as valuable tools for both in vitro and in vivo testing of novel therapeutic agents. Notably, the SP-10 cell line model represents one of the few documented cases isolated from a genuine "classic" MPNST.
2025-04-26 | Pedicled Vascularized Common Peroneal Nerve Graft in Sciatic Nerve Reconstruction With Involvement of Inner Pelvic Lumbar and Sacral Nerve Roots: A Case Report and Literature Review.
Long segment losses exceeding 10 cm in the sciatic nerve are challenging in both the reconstructive techniques and optimizing sensory and motor function recovery. This case report and literature review describes our experience of using a pedicled vascularized common peroneal nerve graft to repair a 14-cm sciatic nerve defect, involving L4, L5, and S1 nerve roots. Additionally, we conducted a literature review of various types of nerve autografts for large sciatic nerve defects, summarizing their characteristics and outcomes to aid clinicians in decision-making and expected results in different scenarios. The patient, a 23-year-old female diagnosed with neurofibromatosis type I, underwent R0 tumor resection of the proximal left sciatic nerve due to a malignant peripheral nerve sheath tumor. She received an ipsilateral pedicled vascularized common peroneal nerve graft. The reconstruction included the L4, L5, and S1 nerve roots beyond the greater sciatic foramen into the inner pelvis. The patient's postoperative course was uneventful. At the 26-month follow-up, she showed MRC grade 4/5 strength in hamstrings with 90°knee flexion and a steady gait pattern. At the 32-month follow-up, she could ambulate very well with an ankle-foot orthosis. The outcomes support the use of a pedicled vascularized common peroneal nerve graft in a single-staged surgery to restore motor function for large sciatic nerve defects. Our literature review revealed that in cases where sural nerves are insufficient or injured for sciatic nerve reconstruction, the common peroneal nerve is a viable alternative to help patients regain functional independence.
2024-04-08 | Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient-derived orthotopic xenografts, cell lines and tumor entities.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heterogeneity could be partly responsible for the observed disparity in treatment response due to the inherent diversity of the preclinical models used. For several years, our group has been generating a large patient-derived orthotopic xenograft (PDOX) MPNST platform for identifying new precision medicine treatments. Herein, we describe the expansion of this platform using six primary tumors clinically diagnosed as MPNSTs, from which we obtained six additional PDOX mouse models and three cell lines, thus generating three pairs of in vitro-in vivo models. We extensively characterized these tumors and derived preclinical models, including genomic, epigenomic, and histological analyses. Tumors were reclassified after these analyses: three remained as MPNSTs (two being classic MPNSTs), one was a melanoma, another was a neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell neoplasm, and, finally, the last was an unclassifiable tumor bearing neurofibromin-2 (NF2) inactivation, a neuroblastoma RAS viral oncogene homolog (NRAS) oncogenic mutation, and a SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (SMARCA4) heterozygous truncated variant. New cell lines and PDOXs faithfully recapitulated histology, marker expression, and genomic characteristics of the primary tumors. The diversity in tumor identity and their specific associated genomic alterations impacted treatment responses obtained when we used the new cell lines for testing compounds against known altered pathways in MPNSTs. In summary, we present here an extension of our MPNST precision medicine platform, with new PDOXs and cell lines, including tumor entities confounded as MPNSTs in a real clinical scenario. This platform may constitute a useful tool for obtaining correct preclinical information to guide MPNST clinical trials.
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2026-09-21 | A Reproducible Transcriptomic Program of Neurofibroma-to-Malignant Peripheral Nerve Sheath Tumor Transformation.
Malignant peripheral nerve sheath tumor (MPNST) carries the highest excess mortality of the cancers associated with neurofibromatosis Type 1, and usually arises from a neurofibroma. We asked whether the transcriptomic differences that distinguish MPNST from neurofibroma reproduce across independent cohorts, and whether a compact score derived from them transports between platforms. We meta-analyzed five public discovery cohorts of primary nerve-sheath tissue (113 MPNST, 79 neurofibromas; 3 platforms) and held out a sixth, independently generated cohort. Neurofibroma and MPNST tissue differed at 1489 genes in two opposing themes: up-regulated mitotic machinery (TOP2A, EZH2, AURKA) and loss of Schwann-cell identity (the transcription factors SOX10 and EGR2, and the myelin genes PMP2 and MPZ). These differences were reproducible. Among the significant genes assayed in all five cohorts, almost all changed in the same direction in everyone, and 93.3% of those detectable in the held-out cohort agreed in direction. Leave-one-cohort-out re-derivation of the pipeline gave a mean AUC of 0.90 across five folds (per-fold 0.84 to 0.97). CD276 (B7-H3) was selectively up-regulated, whereas CD274 and PDCD1LG2 were not. The myelin marker PMP2, a readout chosen retrospectively after the held-out results were known, separated MPNST from neurofibroma in that cohort but left atypical and conventional neurofibromas unseparated (AUC 0.67, p = 0.10). A program score derived without the discovery cohort carrying survival data was associated with shorter survival there, an exploratory single-cohort association. The composition of a compact score varied with platform and preprocessing, so no fixed single-sample classifier is warranted.
2026-09-18 | Pediatric Superficial Malignant Perineurioma/Perineuriomatous Malignant Peripheral Nerve Sheath Tumor of the Groin With NF1 Loss: A Case Report and Focused Review of the Literature.
Malignant perineurioma, also referred to as perineuriomatous malignant peripheral nerve sheath tumor (MPNST), is an exceptionally rare neoplasm with limited clinicopathologic characterization, particularly in children. We report a 12-year-old boy with a 3.0-cm superficial right groin lesion. Histopathologic examination showed a spindle cell neoplasm with fascicular-to-swirling architecture in myxoid to collagenous stroma, moderate cytologic atypia and nuclear variability, mitotic activity, focal necrosis, and admixed inflammation. Epithelial membrane antigen, GLUT1, and claudin-1 positivity supported perineurial differentiation, while a broad negative immunohistochemical panel helped exclude potential mimics. Tumor-only sequencing demonstrated 17q loss with focal homozygous NF1 deletion, a BRCA2 frameshift, and low tumor mutational burden (3.4 mutations/Mb); RNA sequencing identified no pathogenic gene fusion. These molecular findings were interpreted as adjunctive rather than independently diagnostic. The tumor extended to the inked specimen edge, and subsequent management and follow-up information was unavailable. To our knowledge, this is the first reported superficial cutaneous malignant perineurioma/perineuriomatous MPNST in a pediatric patient.
2026-09-01 | Real-world experience with ipilimumab in combination with nivolumab in advanced sarcoma: a retrospective analysis including ultra-rare sarcomas.
Patients with locally advanced or metastatic sarcoma have a poor prognosis and limited efficacious treatment options. Phase 2 trials have demonstrated efficacy for the combination of ipilimumab and nivolumab in select sarcoma histologies, but real-world data is limited. In this single-institution retrospective analysis, patients with metastatic or unresectable sarcoma treated with the combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab were assessed for response by iRECIST criteria and were correlated with clinical outcomes. The Kaplan-Meier method was used for survival analysis. From 2019 to 2024, 90 patients with advanced sarcoma were treated with combination ICI and were evaluable for outcomes. The observed objective response rate (ORR) was 16.7% with clinical benefit rate (CBR) of 30%. The best response was partial response (PR) in 14.4%, stable disease (SD) in 23.3%, and progressive disease (PD) in 62.2%. Median overall survival (OS) (95% confidence interval [CI] 14.4-NE months) and median progression-free survival (mPFS) (95% CI, 9.6-NE months) were not reached for patients achieving an objective response. OS was superior in patients who experienced immune-related adverse events (irAEs). Both mPFS and median overall survival were superior in patients with thyroid irAEs. Highest ORR were seen in angiosarcoma, malignant peripheral nerve sheath tumor, leiomyosarcoma, undifferentiated pleomorphic sarcoma, and chondrosarcoma. Real-world analysis of combination ICI in a large cohort of heavily pretreated patients with advanced sarcomas demonstrates clinical benefit in a meaningful number of patients, including historically unresponsive histologies, though predictive factors remain elusive. The development of irAEs, specifically thyroid dysfunction, was associated with improved survival. Sustained responses were observed in patients who achieved an objective response.
2026-08-02 | Intratumoural plasma cells mediate a pro-inflammatory response to kinase inhibition and successful immune checkpoint blockade therapy in malignant peripheral nerve sheath tumours.
The role of intratumoural plasma cells in immune checkpoint blockade (ICB) therapy has never been tested although their presence is linked with improved response and survival in people with cancer. Malignant peripheral nerve sheath tumours (MPNSTs) are deadly sarcomas with minimal responsiveness to ICB therapies. Strikingly, drugs inhibiting cyclin-dependent kinases 4/6 (CDK4/6) and MEK sensitise de novo MPNSTs to immunotherapy targeting programmed death-ligand 1 (PD-L1), which correlates with increased intratumoural plasma cells. Here, we tested if plasma cells mediate MPNST response to anti-PD-L1 therapy and how they modulate tumour immune responsiveness to CDK4/6-MEK inhibition. Anti-tumour activity of PD-L1 inhibition, with or without CDK4/6-MEK inhibition, was measured in de novo MPNSTs within wild-type versus plasma cell-deficient mice. Plasma cell-dependent effects of CDK4/6-MEK inhibition on priming the MPNST immune environment were determined by single cell transcriptomics and immune cell analyses. Plasma cell-deficient MPNSTs failed to respond to anti-PD-L1 monotherapy and were no longer sensitised by CDK4/6-MEK inhibition to immunotherapy. Following kinase inhibitor treatment, plasma cells were necessary for a pro-inflammatory response marked by increased tumour infiltration and activation of natural killer (NK) and CD8+ T cells, major histocompatibility class I antigen presentation, and decreased M2 macrophages. By comparison, elevated CD4+ T cell and B cell infiltration dominated the plasma cell knockout phenotype. Plasma cells favourably remodel the tumour immune environment for anti-tumour immunity and are critical for successful ICB therapy in MPNSTs. These findings may inform ICB treatment strategies and patient stratification for therapy of many tumour types. This research was supported by University of Iowa Sarcoma Research Program awards, the Gilbert Family Foundation, and NIH grants T34-GM141143, T32-GM067795, F31-CA281312, P30-CA086862, and R01-NS119322.
2026-06-30 | Primary colonic malignant peripheral nerve sheath tumor with biphasic morphology: A case report
BACKGROUNDMalignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive soft tissue sarcoma, in which primary colonic involvement is exceptionally uncommon.Previously reported colonic cases have mostly shown a conventional spindle-cell morphology, while cases with unusual histologic patterns remain poorly characterized. CASE SUMMARYIn the reported case, a 75-year-old man presented with intermittent right upper abdominal pain and abdominal distension.He underwent contrast-enhanced computed tomography, which revealed a large invasive mass extending from the right subphrenic region to the gallbladder fossa, with indistinct borders from the adjacent liver, duodenum, and pancreatic head.Exploratory laparotomy and right hemicolectomy were performed.Histologically, the tumor displayed a biphasic pattern composed of approximately a 30% spindle-cell component and 70% small round-cell component.The spindle-cell areas consisted of intersecting fascicles of atypical spindle cells with hyperchromatic nuclei and brisk mitotic activity, while the small round-cell areas were composed of densely packed primitive-looking cells with scant cytoplasm and hyperchromatic nuclei.Tumor necrosis was also observed.Immunohistochemically, S-100 showed patchy positivity in approximately 40% of tumor cells, while cytokeratins, smooth muscle markers, melanocytic markers, and Ewing sarcoma-related markers were negative.The Ki-67 Labeling index was very high, at approximately 90%, and a complete loss of H3K27me3 was observed in all the tumor cell nuclei.Based on the morphologic features, immunophenotype, and exclusion of major differential diagnoses, the lesion was diagnosed as a primary sporadic high-grade MPNST of the colon.Despite complete resection of the tumor with negative margins, the patient rapidly developed massive pleural and peritoneal effusions after surgery, which then progressed to respiratory failure, and he ultimately died on postoperative day 13. 4 / 36 CONCLUSION Primary colonic MPNST may present with an atypical biphasic spindle and small round cell morphology, creating a potential diagnostic overlap with other high-grade mesenchymal malignancies of the colon.In challenging cases, a consideration of the H3K27me3 status may provide important ancillary diagnostic support.Even after complete resection, tumors with high-risk pathologic features may follow an extremely aggressive clinical course, underscoring the need for early recognition, accurate pathologic diagnosis, close postoperative surveillance, and multidisciplinary management.
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2025-05-15 | Supplementary Figure S6 from DLK1 Distinguishes Subsets of NF1-Associated Malignant Peripheral Nerve Sheath Tumors with Divergent Molecular Signatures
<p>In vitro overexpression of DLK1 in human PNF and MPNST cell lines</p>
2024-11-01 | BIOM-37. EXPLORING L-TYPE AMINO ACID TRANSPORTER 1 (LAT1) AS A DIAGNOSTIC MARKER AND THERAPEUTIC TARGET IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNST)
Abstract OBJECTIVES Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that frequently arise from benign plexiform neurofibromas (PN). Approximately half of MPNST are associated with Neurofibromatosis type 1 (NF1). Despite partial elucidation of the molecular mechanisms underlying MPNST, diagnosis remains challenging, and prognosis is poor. Previously, we found that MPNST cells have elevated βIII-spectrin, a cytoskeletal protein involved in cell morphology and regulation of transporters, including L-type Amino Acid Transporter 1 (LAT1). LAT1 facilitates transport of large neutral amino acids and is upregulated in other cancer types. Our objective is to investigate LAT1 as a diagnostic marker and therapeutic target for MPNST. METHODS Gene and protein expression were determined by qPCR and WES protein analysis, respectively. The effect of shRNA knockdown of LAT1 in MPNST cells was assessed using IncuCyte proliferation assays as well as multiple mouse models. Tumor uptake of [18F] FDOPA, primarily transported by LAT1, in MPNST PDX tumors was assessed using PET/CT imaging. RESULTS LAT1 was expressed in MPNST (n=14) vs. benign PN tissues (n=6). Additionally, in human and murine MPNST cells, shRNA-mediated knockdown of LAT1 suppressed proliferation of MPNST cells in vitro and tumor growth in vivo. In a subcutaneous tumor growth model, intratumor injection of shLAT1 lentivirus reduced tumor volume to approximately 50% of control. Furthermore, uptake of [18F] FDOPA by LAT1 in MPNST PDX tumors was detected by PET/CT imaging. WU-356 PDX tissues exhibited higher LAT1 expression as well as increased uptake of [18F] FDOPA in tumors. Conversely, PET imaging showed significantly lower uptake of [18F] FDOPA in LAT1 knockdown tumors (p<0.05). CONCLUSIONS These results suggest that LAT1 promotes the growth and survival of MPNST cells. In addition, these findings demonstrate the potential use of LAT1 and the radiotracer [18F] FDOPA as a diagnostic biomarker in the management of MPNST.
2024-07-12 | The Use of Hexokinase 2-Displacing Peptides as an Anti-Neoplastic Approach for Malignant Peripheral Nerve Sheath Tumors.
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.
2024-01-11 | Deciphering the Immune Microenvironment of NF1-associated Peripheral Nerve Sheath Tumors: Identifying Early Biomarkers of Disease Progression and Malignant Transformation
Background/Objective:Neurofibromatosis type 1 (NF1) is a multisystem disorder that affects ~1/3000 newborns. Plexiform neurofibromas (PN) are present in about half of cases and can transform (lifetime risk of 8-13%) into malignant peripheral nerve sheath tumor (MPNST), a highly aggressive and metastatic sarcoma with poor survival. Unfortunately, there are currently no reliable biomarkers to identify PN at risk of undergoing malignant transformation. Our research has revealed that a subset of benign-appearing and atypical PN exhibit deregulated immune surveillance and T-cell infiltration that precede malignant transformation. In this study, we are analyzing tumor microenvironment and immune landscape in NF1-related tissue specimens to identify biomarkers of disease progression. To power these studies, this project focused on constructing a dataset of NF1-related samples to be analyzed. Methods:701 patients were identified via Cerner billing codes and pathology archives. De-identified clinical data, including presenting symptoms, relevant clinical history, pathology diagnoses, disease features, prior chemotherapeutics/radiation, prior gene profiling, and imaging features were collected. Results: We selected 86 patients with a total of 175 samples. 81% of patients had a clinical diagnosis of NF1, and 6% had a history of MPNST. Out of the 175 samples, 54 were in the head and neck, 42 in the thorax, 28 in the lower extremity, 27 in the upper extremity, 26 in the pelvis/abdomen, and 15 in the paraspinal region. The leading causes of procedures were pain (41%), growth (40%), and concern for malignancy (27%). The most common tissue diagnoses were neurofibroma (51.4%), PN (20%), and undefined-grade MPNST (11%). Out of the 46 MPNSTs, 30 were primary tumors, 4 metastases, and 12 local recurrences. Conclusion and Potential Impact:The results of this study will provide valuable insights to inform preclinical models of NF1-tumorigenesis to validate these findings and identify novel treatment approaches for individuals affected by these rare but devastating tumors.
2023-03-28 | Delineating the tumour-regulatory roles of EYA4.
Eyes absent homolog 4 (EYA4) is a protein that regulates many vital cellular processes and organogenesis pathways. It possesses phosphatase, hydrolase, and transcriptional activation functions. Mutations in the Eya4 gene can cause sensorineural hearing loss and heart disease. In most non-nervous system cancers such as those of the gastrointestinal tract (GIT), hematological and respiratory systems, EYA4 acts as a putative tumor suppressor. However, in nervous system tumors such as glioma, astrocytoma, and malignant peripheral nerve sheath tumor (MPNST), it plays a putative tumor-promoting role. EYA4 interacts with various signaling proteins of the PI3K/AKT, JNK/cJUN, Wnt/GSK-3β, and cell cycle pathways to exert its tumor-promoting or tumor-suppressing effect. The tissue expression level and methylation profiles of Eya4 can help predict the prognosis and anti-cancer treatment response among cancer patients. Targeting and altering Eya4 expression and activity could be a potential therapeutic strategy to suppress carcinogenesis. In conclusion, EYA4 may have both putative tumor-promoting and tumor-suppressing roles in different human cancers and has the potential to serve as a prognostic biomarker and therapeutic agent in various cancer types.
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Drug Discovery Landscape
1 orphan drug designation for Malignant peripheral nerve sheath tumor.
1 orphan drug designation for Malignant peripheral nerve sheath tumor.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Small molecule inhibitor of PRMT5 (protein arginine methyl transferase 5) | small molecules | FDA | Tango Therapeutics |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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