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
998 drug discovery papers related to Malignant peripheral nerve sheath tumor, with 4 first-in-class and 16 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
998 drug discovery papers related to Malignant peripheral nerve sheath tumor, with 4 first-in-class and 16 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-06-18 | Induced pluripotent stem cell-derived models of malignant nerve sheath tumor progression mimic glial to neuro-mesenchymal transition and uncover therapeutic opportunities.
Neurofibromatosis Type 1 (NF1) predisposes to peripheral nerve tumor development. The progression from a benign plexiform neurofibroma (PNF) towards a deadly malignant peripheral nerve sheath tumor (MPNST) is not completely understood but commonly involves the sequential loss of NF1, CDKN2A, and polycomb repressive complex 2 (PRC2). Here we use an iPSC-derived neural crest (NC) model to reproduce this malignant transformation through gene editing. NF1-CDKN2A double-knockout (2KO) NCs form neurofibroma-like tumors in vivo, requiring inactivation of p14ARF and p16INK4a. Additional PRC2 loss (3KO) disrupts pluripotency and induces mesenchymal stem cell-like features. 3KO NCs undergo global chromatin reorganization that prevents gliogenesis by SOX10 silencing and activates neuro-mesenchymal transcriptional programs recapitulating PNF-ANNUBP-MPNST progression. Upon nerve engraftment, 3KO NC spheres form MPNST-like tumors in vivo, mimicking an early-stage MPNST. Furthermore, we use the 3D NC spheroid models to discover drugs targeting MPNSTs through high-throughput screening of epigenetic compounds. Poly(ADP-ribose) polymerase inhibitors (PARPi) exhibit selective efficacy in PRC2-deficient NC spheroids and Olaparib-Selumetinib combination is well tolerated and significantly suppresses tumor growth in a human MPNST PDX mouse model.
2026-06-04 | Selective Pyroptosis in NF1-Deficient Cells through PKCδ Agonism.
Pyroptosis, a lytic and immunogenic form of cell death, holds broad therapeutic potential, yet its selective induction in specific cell populations remains a fundamental challenge. Loss of the NF1 tumor suppressor, one of the most frequent events across pediatric and adult cancers, elevates RAS-GTP and drives tumorigenesis through hyperactivated RAS signaling. Here we demonstrate that protein kinase Cδ (PKCδ) agonism selectively triggers pyroptosis in NF1-deficient cells by exploiting their dependency on KRAS. PKCδ directly phosphorylates KRAS at S39 and S181, inducing KRAS-GDP accumulation and driving endoplasmic reticulum translocation. The dually phosphorylated KRAS-GDP interacts with caspase-8 and competitively displaces inhibitory BCL2, promoting caspase-8/caspase-3/gasdermin-E-mediated pyroptosis. This vulnerability is conserved across multiple NF1-deficient tumor types, and PKC agonism suppresses NF1-deficient neurofibroma and malignant peripheral nerve sheath tumor growth in vivo . These findings establish the inactive KRAS-GDP as a functionally active signaling molecule and PKCδ agonism as a selective therapeutic strategy for NF1-deficient cancers.
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.
2026-06-18 | Induced pluripotent stem cell-derived models of malignant nerve sheath tumor progression mimic glial to neuro-mesenchymal transition and uncover therapeutic opportunities.
Neurofibromatosis Type 1 (NF1) predisposes to peripheral nerve tumor development. The progression from a benign plexiform neurofibroma (PNF) towards a deadly malignant peripheral nerve sheath tumor (MPNST) is not completely understood but commonly involves the sequential loss of NF1, CDKN2A, and polycomb repressive complex 2 (PRC2). Here we use an iPSC-derived neural crest (NC) model to reproduce this malignant transformation through gene editing. NF1-CDKN2A double-knockout (2KO) NCs form neurofibroma-like tumors in vivo, requiring inactivation of p14ARF and p16INK4a. Additional PRC2 loss (3KO) disrupts pluripotency and induces mesenchymal stem cell-like features. 3KO NCs undergo global chromatin reorganization that prevents gliogenesis by SOX10 silencing and activates neuro-mesenchymal transcriptional programs recapitulating PNF-ANNUBP-MPNST progression. Upon nerve engraftment, 3KO NC spheres form MPNST-like tumors in vivo, mimicking an early-stage MPNST. Furthermore, we use the 3D NC spheroid models to discover drugs targeting MPNSTs through high-throughput screening of epigenetic compounds. Poly(ADP-ribose) polymerase inhibitors (PARPi) exhibit selective efficacy in PRC2-deficient NC spheroids and Olaparib-Selumetinib combination is well tolerated and significantly suppresses tumor growth in a human MPNST PDX mouse model.
2026-06-04 | Selective Pyroptosis in NF1-Deficient Cells through PKCδ Agonism.
Pyroptosis, a lytic and immunogenic form of cell death, holds broad therapeutic potential, yet its selective induction in specific cell populations remains a fundamental challenge. Loss of the NF1 tumor suppressor, one of the most frequent events across pediatric and adult cancers, elevates RAS-GTP and drives tumorigenesis through hyperactivated RAS signaling. Here we demonstrate that protein kinase Cδ (PKCδ) agonism selectively triggers pyroptosis in NF1-deficient cells by exploiting their dependency on KRAS. PKCδ directly phosphorylates KRAS at S39 and S181, inducing KRAS-GDP accumulation and driving endoplasmic reticulum translocation. The dually phosphorylated KRAS-GDP interacts with caspase-8 and competitively displaces inhibitory BCL2, promoting caspase-8/caspase-3/gasdermin-E-mediated pyroptosis. This vulnerability is conserved across multiple NF1-deficient tumor types, and PKC agonism suppresses NF1-deficient neurofibroma and malignant peripheral nerve sheath tumor growth in vivo . These findings establish the inactive KRAS-GDP as a functionally active signaling molecule and PKCδ agonism as a selective therapeutic strategy for NF1-deficient cancers.
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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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Small molecule inhibitor of PRMT5 (protein arginine methyl transferase 5) | small molecules | FDA | 2022-07-25 | — | Tango Therapeutics |
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