RARE DISEASE
Full schwannomatosis
Full schwannomatosis
Full schwannomatosis
Synonyms: Full NF3, Full SWN, Full neurofibromatosis type 3, Neurilemmomatosis, Nonmosaic schwannomatosis
Synonyms: Full NF3, Full SWN, Full neurofibromatosis type 3, Neurilemmomatosis, Nonmosaic schwannomatosis
Synonyms: Full NF3, Full SWN, Full neurofibromatosis type 3, Neurilemmomatosis, Nonmosaic schwannomatosis
Drug discovery
1
drug
With orphan designation
Overview
Full schwannomatosis is a rare tumor predisposition syndrome characterized by multiple benign schwannomas affecting spinal, peripheral, and cranial nerves (excluding vestibular nerves). Chronic pain is the hallmark symptom, often refractory to treatment. Unlike NF2, life expectancy is normal, but morbidity is substantial due to tumor-related complications. Caused by SMARCB1 or LZTR1 mutations in 70–85% of familial cases and 30–40% of sporadic cases [1][11][12]. Diagnosis requires exclusion of vestibular schwannomas [1][16].
Therapies
Pain management: First-line use of gabapentin, tricyclic antidepressants, or SNRIs [3][8][13].
Surgery: Reserved for symptomatic tumors, though recurrence occurs in 75% of cases and risks nerve damage [6][13].
Surveillance: MRI monitoring for new tumors; clinical trials exploring molecular therapies (e.g., MEK inhibitors) [5][18].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare skin diseases, rare transplant-related disorders
Research Papers
130 drug discovery papers about Full schwannomatosis, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
130 drug discovery papers about Full schwannomatosis, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-02-27 | Deciphering and Targeting the Schwannoma-Neuron-Macrophage Crosstalk for the Treatment of Schwannomatosis and Associated Pain.
Non-NF2 Schwannomatosis (SWN) is a genetic disorder characterized by multiple non-malignant schwannomas growing on the spine and peripheral nerves. Patients with SWN overwhelmingly present with intractable chronic pain. There are no FDA-approved drugs to halt tumor growth or alleviate pain. Research on SWN is hindered by the lack of clinically relevant models. We established patient-derived SWN cell lines from patients with varying pain levels and developed orthotopic patient-derived xenograft models that reproduce patients' pain responses. We further developed a novel dorsal root ganglia (DRG) imaging model for longitudinal intravital imaging of macrophage infiltration into the DRG and sensory neuron pain response. Leveraging these novel models, we found that Schwannomas grown distantly in the peripheral nerve caused an influx of macrophages into the DRG. These macrophages in the DRG caused pain via overproducing IL-6. Treatment with anti-IL-6 antibody reduced pain but had modest efficacy in tumor control. We identified epidermal growth factor receptor (EGFR) signaling as a key driver of schwannoma growth and an escape mechanism from anti-IL6 treatment. Finally, we found that combining IL-6 and EGFR blockade effectively controlled pain and tumor growth simultaneously in SWN models. In summary, we elucidated the cellular and molecular crosstalk between schwannoma (HMGB1), neuron (CCL2), and macrophage (IL-6) in driving pain, and identified the EGF signaling pathway as a driver of SWN tumor progression, thereby uncovering novel therapeutic targets that may improve clinical management of SWN.
2026-02-16 | A cochlea-sparing strategy for non-invasive control of intracranial schwannomas via peripheral irradiation and anti-PD-1 therapy enhanced by STING activation.
Rationale: NF2-related schwannomatosis (NF2-SWN) is a progressive neurological disorder with a hallmark of bilateral vestibular schwannomas (VSs), leading to irreversible hearing loss and reduced quality of life. To date, the FDA has not approved any pharmacological therapies for treating VS or hearing loss. While radiotherapy (RT) is the standard treatment for growing VSs, it often exacerbates hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their efficacy in non-malignant tumors like VS remains largely unexamined. Methods: We used immune-competent VS mouse models to assess the efficacy of combined anti-PD1 (αPD1) and RT treatment, tumor growth, and hearing preservation. Results: We found three significant therapeutic benefits: i) RT induces immunogenic cell death and activates the STING pathway, enhancing αPD1 efficacy and generating long-term immune memory, ii) The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) RT to peripheral nerve tumor induces a systemic abscopal effect, which enhances αPD-1 efficacy to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. Conclusion: Our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and NF2-SWN.
2026-02-12 | NKG2D upregulation sensitizes tumors to combined anti-PD1 and anti-VEGF therapy and prevents hearing loss.
NF2-related schwannomatosis (NF2-SWN) is a debilitating condition, characterized by bilateral vestibular schwannomas (VSs) that progressively cause irreversible sensorineural hearing loss. Current management relies on surgery or radiotherapy, while bevacizumab (αVEGF) is used off-label, with variable and often transient efficacy. Effective therapies that durably suppress tumor growth and preserve hearing are urgently needed. Although immune checkpoint inhibitors have transformed cancer treatment, their efficacy in non-malignant tumors such as VS remains unclear. Here, we evaluate combined anti-PD1 (αPD1) and αVEGF therapy in two syngeneic, immune-competent VS models. Combination treatment significantly outperforms either monotherapy, inhibiting tumor growth and preventing hearing loss. Mechanistically, αVEGF enhances αPD1 efficacy by normalizing tumor vasculature, improving drug delivery and immune cell infiltration, and promoting cytotoxicity of T and NK cells via NKG2D upregulation. Combined treatment effectively controls tumor growth that progresses despite anti-VEGF therapy. These findings support αPD1 and αVEGF combination therapy as a promising strategy for NF2-SWN.
2025-10-01 | P14.18.A SCHWANNOMAS DISPLAY CONSERVED CELLULAR STATES AND PREFERENTIAL MHC CLASS II ANTIGEN PRESENTATION ACROSS DIFFERENT GENETIC BACKGROUNDS AND ANATOMIC LOCATIONS
Abstract BACKGROUND Despite being associated with molecular alterations in the NF2 gene, there is limited understanding of the gene expression programs that govern the behavior of schwannomas—both in sporadic cases and in patients with schwannoma predisposition syndromes—and how these programs relate to tumor anatomic location. MATERIAL AND METHODS We characterized the transcriptional heterogeneity of schwannomas across different genetic backgrounds and anatomic locations at single-cell resolution. Tumor samples from patients undergoing resection for symptomatic schwannoma were dissociated and processed for whole-transcriptome profiling using Smart-seq2. Our cohort included 22 schwannomas: 5 from schwannomatosis patients, 11 from neurofibromatosis type 2 (NF2) patients, and 6 sporadic tumors (3 post-radiation). Anatomically, 12 tumors were from cranial nerves (11 vestibular, 1 accessory), and 10 from spinal or peripheral nerves. RESULTS We profiled 11,373 cells, including 4,725 neoplastic cells and various non-neoplastic populations. Copy number alteration analysis revealed intratumoral polyclonality. Non-negative matrix factorization identified six conserved transcriptional metaprograms related to stress response, myelin production, antigen presentation, interferon signaling, glycolysis, and extracellular matrix remodeling. Notably, schwannomas exhibited a distinctive antigen presentation metaprogram, enriched for MHC class II genes (e.g., HLA-DRA, HLA-DRB1). Additionally, we observed a distinct interferon signaling program, which was conserved across most tumors but attenuated in vestibular schwannomas, indicating a potential mechanism of regional immune evasion. Comparison with pan-cancer data confirmed the relative uniqueness of these immune-related programs to schwannomas. CONCLUSION We provide a comprehensive single-cell transcriptomic analysis of schwannomas across genetic and anatomic contexts. Our findings reveal unique, conserved immune-related transcriptional programs, particularly involving antigen presentation and interferon signaling, which may contribute to tumor immune evasion and inform future immunotherapeutic strategies.
2025-09-22 | Focused ultrasound-mediated drug delivery of bevacizumab in treating NF2-related schwannomatosis in an animal model
Neurofibromatosis type 2 (NF2)-related schwannomatosis is an autosomal dominant genetic disorder characterized by the development of cranial and peripheral nerve schwannomas, including bilateral vestibular schwannomas and dorsal root ganglion schwannomas along the spinal axis, both of which are associated with substantial morbidity. Current therapeutic strategies comprise surgical resection, radiotherapy, and systemic administration of bevacizumab; however, these approaches are frequently limited by high recurrence rates and morbidity. In this study, a transgenic murine model (Postn-Cre;Nf2flox/flox) was employed to investigate the combined effect of intraperitoneally administered human bevacizumab (5 mg/kg b. w.) and focused ultrasound (FUS) on drug delivery and tumor growth in DRG schwannomas. ELISA-based analysis demonstrated a 2.88-fold increase in intratumoral bevacizumab concentration following the combined application of human bevacizumab and FUS, compared to bevacizumab alone. Tumor growth was assessed using 7-tesla MRI of the spine with intravenous gadolinium contrast, and outcomes were compared across five experimental groups: 1) human bevacizumab alone, 2) murine bevacizumab alone, 3) human bevacizumab combined with FUS, 4) FUS alone, and 5) untreated controls. Treatments, including drug administration and FUS exposure, were performed three times at two-week intervals. Notably, the combined treatment group (human bevacizumab + FUS) exhibited a trend toward tumor size reduction.
gene therapies
2026-03-24 | Malignant peripheral nerve sheath tumors arising in SMARCB1-associated schwannomatosis: illustrative cases.
Schwannomatosis is a rare tumor predisposition syndrome characterized by benign peripheral nerve sheath tumors in the absence of bilateral vestibular schwannomas. In rare cases, malignant peripheral nerve sheath tumors (MPNSTs) may arise with schwannomatosis, particularly with SMARCB1 mutations. These malignancies pose significant diagnostic and therapeutic challenges and a poor prognosis. The authors present 2 cases of high-grade MPNST with SMARCB1-associated schwannomatosis. Both presented with rapidly enlarging and concerning imaging features, including heterogeneous enhancement, central necrosis, and low apparent diffusion coefficient values. Histopathological analysis confirmed high-grade MPNST with elevated mitotic activity and loss of H3K27me3. Both patients underwent en bloc resection with negative margins. One patient remains disease free at 5 years; the other patient developed metastatic recurrence and died. A systematic review identified 20 cases in the literature. These cases emphasize clinical vigilance for malignant transformation in schwannomatosis, particularly with rapidly enlarging lesions or new neurological symptoms. MRI and FDG-PET can aid in identifying concerning features. Despite margin-negative resection, recurrence and metastasis may occur, reflecting the tumor's aggressive biology. Genetic counseling may be considered in SMARCB1-associated cases. While malignant transformation is much more common in NF1 lesions, rare cases do arise in schwannomatosis, requiring close surveillance and multidisciplinary management. https://thejns.org/doi/10.3171/CASE25610.
2026-01-22 | [Schwannomatosis diagnosed from an approximately 30-year history of multiple mononeuropathy accompanied by multiple cauda equina nodules: a case report].
A 51-year-old woman presented with left drop foot at age 20, numbness in the right fourth and fifth fingers at age 45, and numbness in both lower extremities at age 51. Lumbar MRI revealed multiple cauda equina nodules, while ultrasonography of the peripheral nerve identified enlarged nerve bundles in several locations, including the right ulnar and left peroneal nerves. Nerve conduction studies and upper extremity MRI findings were consistent with these observations, and head MRI confirmed the absence of auditory schwannomas. Schwannomatosis (SWN) is a rare disease characterized by the formation of multiple peripheral schwannomas, associated with genetic abnormalities such as SMARCB1 and LZTR1. When multiple peripheral nerve tumors are detected, SWN should be considered as part of the differential diagnosis.
2026-01-12 | Central nervous system schwannoma, VGLL-fused (EWSR1::VGLL1 fusion) with neuroblastoma-like cell dense areas in the frontal lobe of a young man with schwannomatosis due to a germline LZTR1 mutation.
We report a central nervous system schwannoma, VGLL-fused in a young man's frontal lobe. Somatic abnormalities included an EWSR1::VGLL1 fusion, which incorporated the entire translated region of VGLL1, but excluded most domains of EWSR1. The tumor histologically merged with the brain, and showed both schwannoma-like and neuroblastoma-like areas. A germline LZTR1 mutation was subsequently identified, implying the patient suffered from schwannomatosis.
2025-08-12 | SMARCB1-related schwannomatosis and other SMARCB1-associated phenotypes: clinical spectrum and molecular pathogenesis.
SMARCB1 is a core unit of the BAF chromatin remodelling complex and its functional impairment interferes with the self-renewal and pluripotency of stem cells, lineage commitment, cellular identity and differentiation. SMARCB1 is also an important tumour suppressor gene and somatic SMARCB1 pathogenic variants (PVs) have been detected in ~ 5% of all human cancers. Additionally, germline SMARCB1 PVs have been identified in patients with conditions as clinically diverse as Rhabdoid Tumour Predisposition Syndrome type 1 (RTPS1), schwannomatosis and neurodevelopmental disorders such as Coffin-Siris syndrome (CSS). RTPS1 is characterized by the occurrence of highly malignant atypical teratoid rhabdoid tumours (AT/RT) affecting mostly infants, whereas SMARCB1-related schwannomatosis is generally diagnosed after the age of 30 and is characterized by benign schwannomas. Patients with germline SMARCB1 PVs and neurodevelopmental disorders do not usually develop SMARCB1-deficient tumours but instead exhibit severe intellectual disability and congenital malformations. It is intriguing how germline SMARCB1 PVs can be responsible for these very different pathologies. However, a network of different factors has emerged that play important roles in this context. Thus, the tumour phenotype associated with germline SMARCB1 PVs is determined by the nature and location of the SMARCB1 mutation and the timing of SMARCB1 inactivation in specific progenitor cells. Biallelic complete loss of SMARCB1 function during a narrow time window of early embryonic development in neural crest cells is essential for AT/RT development. By contrast, hypomorphic SMARCB1 PVs during later developmental stages affecting more differentiated Schwann cell precursors give rise to schwannomas. However, the loss of the wild-type SMARCB1 allele is insufficient for schwannoma growth which appears to be dependent upon concomitant somatic NF2 PVs in patients with SMARCB1-related schwannomatosis according to the four-hit/three-step model of tumorigenesis. In patients with neurodevelopmental disorders such as CSS, germline PVs would appear to cluster within the C-terminal SMARCB1 domain, interfering with the nucleosomal interactions of SMARCB1 but not with its tumour suppressor activity.
2025-03-07 | Genetic Basis and Clinical Management of Schwannomatosis.
Schwannomatosis (SWN) is now recognized as a broad classification that includes neurofibromatosis (NF) type 2, reflecting their shared genetic and phenotypic characteristics. Previously, SWN and NF type 2 were considered distinct clinical entities; however, the 2022 classification revision has unified them under the umbrella of SWN, with NF type 2 now referred to as NF2-related SWN. SWN arises from mutations in NF2, SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) or LZTR1 (leucine zipper like transcription regulator 1). Recent diagnostic criteria for SWN incorporate molecular classification, including "NF2-related SWN", "SMARCB1-related SWN", "LZTR1-related SWN", "22q-related SWN", "SWN-not otherwise specified", or "SWN-not elsewhere classified". NF2-related SWN is a genetic condition where all individuals with a germline or constitutional NF2 mutation are destined to develop the disease. The pathogenesis of SMARCB1- or LZTR1-related SWN follows a three-step, four-hit model. This involves retention of the mutated germline SMARCB1 or LZTR1 allele in the tumor, loss of the wild-type chromosome 22, and somatic mutation in the NF2 gene. Clinically, NF2-related SWN involves bilateral vestibular schwannomas, with treatment options including microsurgery, radiotherapy, and bevacizumab, each with specific benefits and limitations. Patients with SWN frequently present with chronic pain caused by schwannomas, which often does not correlate with tumor size, location, or burden. Management of SWN is primarily symptom-based. Surgical intervention is reserved for symptomatic lesions, particularly in cases of spinal cord compression or significant functional impairments. Multidisciplinary approaches to pain management are critical for enhancing quality of life. Although malignant transformation of schwannomas is a potential risk, the life expectancy of individuals with SWN is nearly normal. Despite advancements in understanding SWN, further research is necessary to elucidate the underlying genetic mechanisms and to develop targeted therapeutic strategies for this complex disorder.
small molecules
2026-07-15 | Addition of Losartan to Immune Checkpoint Blockade Improves Tumor Control and Neurological Outcomes in Models of NF2-Related Schwannomatosis
NF2 -related schwannomatosis ( NF2 -SWN) is a devastating genetic disorder characterized by the development of bilateral vestibular schwannomas (VSs), which are histologically benign tumors that cause hearing loss and vestibular dysfunction. Currently, there are no FDA-approved pharmacologic therapies for VS or VS-associated hearing loss, representing a major unmet medical need for patients with NF2 -SWN. Although immunotherapy has transformed the treatment of many solid malignancies, its efficacy in VS has not been comprehensively evaluated. We employed VS mouse models that faithfully recapitulate tumor-induced hearing loss and ataxia to evaluate the therapeutic efficacy of anti-PD-1 (αPD-1) immunotherapy alone and in combination with losartan, an angiotensin II type 1 receptor blocker known to reduce tumor extracellular matrix density and normalize tumor vascular perfusion. Tumor growth, survival, hearing function, and neurological outcomes were assessed. Losartan significantly enhanced the intratumoral delivery of αPD-1 antibody and increased immune effector cell infiltration in VS. Consequently, combined losartan and αPD-1 therapy more effectively inhibited tumor growth and prolonged survival compared with monotherapy. In parallel, losartan attenuated inflammatory signaling, thereby reducing neuro-edema. As a result, the combination treatment more effectively prevented tumor-induced hearing loss and alleviated ataxia in the VS mouse model. Targeting the fibrotic tumor microenvironment with losartan sensitizes vestibular schwannomas to immunotherapy and improves neurological outcomes. These findings provide critical preclinical evidence supporting a novel combination strategy using ICIs for NF2 -SWN and offer important insights for the design of future clinical trials aimed at suppressing VS growth while preserving hearing and neurological function.
2026-05-29 | Comprehensive characterization of spinal ependymomas in NF2-Schwannomatosis.
Spinal ependymomas (SE) account for 10% of ependymomas and are the most frequent spinal glial tumors. NF2-related Schwannomatosis (NF2-SWN) patients are predisposed to multiple SE in addition to other tumors, schwannomas and meningiomas. Surgery remains the main treatment option, but mays lead to severe morbidity. In many cases, it is the cystic rather than the solid component of the tumor that drives neurological symptoms and ultimately necessitates surgical intervention. Understanding tumor and associated cyst formation is therefore important to develop new therapeutic approaches. This clinical and radiological study includes 33 NF2-SWN with a long-term follow-up and 11 sporadic SE patients. Tumor and cyst characteristics were assessed, and histopathological analyses performed, including multiplex immunohistochemistry and RNA sequencing. Radiological analysis revealed that peritumoral edema frequently precedes cystic formation. Histological analysis showed that macrophage infiltration, particularly by SPP1-positive macrophages, was associated with cystic growth in NF2-SWN SE. RNAseq analysis identified distinct immune microenvironments differentiating NF2-SWN from sporadic SE, including differences in VEGF-C expression. Consistent with these results, AXITINIB, a selective inhibitor of VEGFR and VEGFR3 which acts as the receptor for VEGF-C, was proposed to a NF2-SWN patient with a progressing cystic SE and resulted in clinical improvement accompanied by a reduction in the peritumoral cyst. These results support a role for VEGF signaling and macrophage-mediated microenvironmental changes in edema and cystic growth of NF2-SWN SE. The observed clinical response to AXITINIB in an index patient suggests that new combinations of anti-angiogenic therapies may represent a promising early targeted approach.
2026-05-13 | TEAD inhibitors synergize with MEK, SHP2 and mTOR inhibitors in NF1 and NF2 cell lines.
Neurofibromatosis type 1 (NF1) and NF2 -related Schwannomatosis ( NF2 -SWN) are both inherited syndromes characterized by Schwann cell tumors. NF1 tumors harbor activated Ras/MEK/ERK, while NF2 -SWN tumors harbor activated mechanosignaling pathways, including Hippo/YAP-TAZ/TEAD. To test combinatorial strategies in tumor cell lines, we first screened a new-generation TEAD inhibitor, VT103, against 123 drugs and then validated the hits with pairwise titrations. VT103 consistently synergized with inhibitors of MEK (trametinib and selumetinib), SHP2 (TNO155) and mTOR (everolimus). The highest synergy ZIP score, calculated using SynergyFinder, was ~65 in the NF2 -SWN cell line SC4, with lower magnitudes in an NF1 cell line.
2026-04-03 | Quantitative imaging of schwannoma captures heterogeneity and accelerates preclinical testing, revealing distinct impacts of targeted therapies.
Schwannomas are debilitating hallmarks of familial schwannomatoses and common sporadic tumors that form on spinal and cranial nerves. Drug-based therapies for schwannoma are desperately needed but their development has been extremely slow and disappointing, impeded particularly by the poorly understood and surprisingly complex and heterogeneous biology of schwannomas, and by the inefficient use of physiologically relevant in vivo preclinical models. We have addressed these gaps by developing a quantitative imaging-centered workflow that allows both a deep analysis of schwannoma development and accelerated preclinical testing in a widely used genetically engineered mouse model of neurofibromatosis type 2-related schwannomatosis (NF2-SWN). We deployed our workflow to study schwannoma development and to test two clinically relevant drugs (rapamycin and brigatinib) head-to-head. Our results uncovered the very early onset of heterogeneity and macrophage recruitment to initiating schwannomas, and the unexpectedly distinct impacts of the two drugs on both, highlighting the value of the pipeline for rapid, innovative future drug-testing.
2026-03-26 | Recurrent Epidermal Growth Factor Receptor 2 (ERBB2) Mutations Drive the Pathogenesis of Multifocal Neurofibroma Variants.
Recurrent Epidermal Growth Factor Receptor 2 (ERBB2) mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by 2 cases of plexiform neurofibromas harboring ERBB2 hotspot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA-sequencing panel. Clinical history, radiologic findings, and follow-up information were retrieved from chart review. Pathologic features, and genomic and germline findings, were reviewed. We identified 5 patients; all except 1 were women, with a median age of 34 years (range: 24-40 years). All revealed multiple PNSTs with a segmental distribution on imaging, including the pelvis (n = 2), upper limb (n = 2), and stomach (n = 1). None of the patients had a family history or displayed clinical features of neurofibromatosis type 1, except for 1 patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n = 4), intraneural with Schwann cell micronodule (n = 2), and diffuse (n = 1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n = 3; exon 20, n = 2; exon 21, n = 1). One additional case had 2 concurrent ERBB2 mutations in exons 20 and 21. On germline testing, only 1 patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, and LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation, 1 being enrolled on an HER2 inhibitor trial for 7 years owing to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications.
cell therapies
2026-08-10 | Deletion of the Salmonella pathogenicity island 2 gene, spiC, in attenuated Salmonella Typhimurium VNP20009 optimizes its potential for bacterial schwannoma therapy.
Recent advances in systems biology and immunotherapy have spurred the use of bacteria as therapeutic vehicles for cancer treatment. Currently, Bacillus Calmette-Guérin remains the only FDA-approved bacterial strain for high-risk, non-muscle-invasive bladder cancer. Although safety concerns have been raised, attenuated Salmonella Typhimurium strains such as VNP20009 have advanced to clinical trials targeting fast-growing human tumors. Notably, this strain induces robust immunological control of slow-growing tumors such as NF2-related schwannomatosis (NF2-SWN) in preclinical murine models. Here, we genetically characterize VNP20009 with the goal of constructing genetically defined attenuated strains that retain its promising therapeutic features while improving safety. Specifically, we investigated the contribution of the Salmonella pathogenicity island I (SPI-1) and SPI-2 type III secretion systems to antitumor efficacy and biosafety. Mutation of the SPI-1 gene sipB, a key structural component required for SPI-1 type III secretion system function, partially reduced tumor control in NF2-SWN murine schwannoma models, suggesting that bacterial invasion alone does not fully account for antitumor activity. In contrast, deletion of the SPI-2 gene spiC, a key effector required for intracellular survival, preserved robust tumor regression in NF2-SWN murine schwannoma models while improving safety and reducing systemic toxicity. To create a genetically defined and tractable platform, we generated two attenuated strains-AST101 and AST101-ΔspiC-which retain key mutations present in VNP20009 but lack ill-characterized background mutations. In the syngeneic NF2-SWN mouse schwannoma model, both strains significantly suppressed tumor growth compared to PBS. Collectively, these findings support the development of rationally engineered Salmonella Typhimurium strains with enhanced safety and preserved antitumor efficacy. Given long-standing safety concerns surrounding the therapeutic use of live bacteria, we constructed a ΔspiC mutant of VNP20009 and demonstrated that it provides a markedly improved safety profile while retaining antitumor efficacy in NF2-related schwannomatosis mouse schwannoma models. In addition, we created two genetically defined Salmonella Typhimurium strains, AST01 and AST01-ΔspiC, which incorporate the key-targeted mutations found in VNP20009 and VNP20009-ΔspiC, respectively. These engineered strains offer a well-defined genetic background, enabling precise investigation of the bacterial traits responsible for Salmonella Typhimurium-mediated tumor control and thus further improvement of attenuated strains optimized for bacteriotherapy of neoplasms.
2025-03-03 | Development of CAR-T cell therapy for NF1/SWN-related nerve sheath tumor treatment.
Neurofibromatosis type 1 (NF1) and schwannomatosis (SWN) are rare genetic disorders with distinct genetic etiologies. Both syndromes are predominantly characterized by the development of multiple benign nerve sheath tumors, which typically arise from cranial/peripheral nerves. The management of NF1/SWN-associated benign nerve sheath tumors pose a substantial clinical challenge. In recent years, immunotherapy has demonstrated significant efficacy in treating various tumors, but its application to NF1/SWN has not been explored. In this study, we first evaluated the feasibility of chimeric antigen receptor (CAR)-T cell therapy for the treatment of benign NF1/SWN-related nerve sheath tumor by analyzing the expression of multiple antigens in 85 tumor samples. Our findings revealed that epidermal growth factor receptor (EGFR/HER1) was highly expressed in most samples, indicating its potential as an ideal target for CAR-T cell therapy. Additionally, TGFβ1 and PDL1, key inhibitory regulators of T cell function within solid tumor microenvironment (TME), were universally overexpressed in these samples, highlighting the immunosuppressive nature of NF1/SWN tumors. To target HER1, we constructed CARs using three distinct scFvs (806, E2 and NEC). All three types of CAR-T cells demonstrated significant tumor-eliminating capability against NF1/SWN tumor cell lines, with 806 CAR-T cells showing the highest efficacy. Considering the immunosuppressive TME, we knocked out TGFBR2 and/or PDCD1 in 806 CAR-T cells using CRISPR/Cas9. Their anti-tumor efficacy was further evaluated using a 3D tumor spheroid model, and the gene-edited 806 CAR-T cells exhibited superior anti-tumor efficacy. In conclusion, we identified HER1 as a target for CAR-T cell therapy in NF1/SWN-related nerve sheath tumors, and developed anti-HER1 CAR-T cells that effectively eliminated NF1/SWN tumor cells, providing a promising therapeutic strategy for patients with these conditions.
2023-01-01 | Allograft nerve repair to prevent sensorimotor loss after nerve sheath tumor resection
Acellularized nerve allografts (ANAs) have been developed as substitutes for nerve autograft to promote nerve regeneration after surgical repair. In this video, the authors demonstrate operative techniques for using ANAs to repair potentially functional nerve fascicles during tumor resection. A 67-year-old female with schwannomatosis requested resection of a painful enlarging mass of the left ulnar nerve proximal to the elbow. During surgery, neuromonitoring suggested that fascicles entering the tumor could be functional. Therefore, nerve allograft was used to repair the transected fascicles. The patient recovered with full strength and sensation in the ulnar distribution, with resolution of her preoperative symptoms. The video can be found here: https://stream.cadmore.media/r10.3171/2022.10.FOCVID22101.
2021-09-14 | Schwann cell‐derived exosomes: Janus‐faced mediators of regeneration and disease
The phenotypic plasticity of Schwann cells (SCs) has contributed to the regenerative potential of the peripheral nervous system (PNS), but also pathological processes. This double-sided effect has led to an increasing attention to the role of extracellular vesicles (EVs) or exosomes in SCs to examine the intercellular communication between SCs and their surroundings. Here, we first describe the current knowledge of SC and EV biology, which forms the basis for the updates on advances in SC-derived exosomes research. We seek to explore in-depth the exosome-mediated molecular mechanisms involved in the regulation of SCs and their microenvironment. This review concludes with potential applications of SC-derived exosomes as delivery vehicles for therapeutics and biomarkers. The goal of this review is to emphasize the crucial role of SC-derived exosomes in the functional integration of the PNS, highlighting an emerging area in which there is much to explore and re-explore.
other
2025-11-14 | NF2 lacking exon 11 induced by antisense gene therapy is able to partially recover merlin deficiency on NF2 -SWN iPSC-derived spheroid model
Abstract NF2 -related Schwannomatosis ( NF2 -SWN) is an inherited autosomal dominant disorder resulting from loss-of-function mutations in the NF2 gene, for which no effective treatment is currently available. Furthermore, truncating variants in NF2 are associated with the severest phenotype compared to in-frame or missense variants. Previously, a shorter NF2 isoform with exon 11 skipped (merlin_e-11), induced through antisense morpholino oligomers (PMOs), was able to partially rescue the deleterious effect of nonsense variants located at that exon in patients’ primary fibroblast. To test the potential of this approach into Schwann cells, those responsible of NF2 -SWN tumours, we developed an iPSC-based model carrying heterozygous and homozygous truncating variants on exon 11 of the NF2 gene and differentiated them to Schwann cells forming spheroids. After 3 days of treatment, merlin_e-11 expression was induced in NF2-deficient cell lines. Furthermore, key pathways associated with NF2-deficiency in schwannomas, such as PI3K/Akt/mTORC and YAP levels, were recovered without signs of toxicity. These results confirm that the PMO treatment induces effective skipping of exon 11 in Schwann cell spheroids, generating an hypomorphic merlin_e-11 that has the capacity to partially rescue merlin-deficiency in NF2 -SWN spheroid cell model and it being a potential treatment of patients harbouring truncating variants located in exon 11.
2024-06-17 | [Features of course of pain syndrome in patients with schwannomatosis].
To identify the characteristics of pain syndrome in patients with schwannomas depending on genetic predisposition. The study included 46 patients with peripheral, spinal and intracranial schwannomas, corresponding to the schwannomatosis phenotype according to the 2022 clinical criteria. All patients underwent sequencing of the LZRT1, Nf2 and SMARCB1 and a copy number study in the NF2. The most severe widespread pain was observed in patients with pathogenic LZRT1 variants, while patients with mosaic variants may not even have local tumor-related pain. Patients with SMARCB1variants may have no pain or have localized pain that responds well to surgical treatment. Further studies of the molecular features of schwannomatosis and driver mutations in the pathogenesis of pain are necessary to improve the effectiveness of pain therapy in this group of patients. Schwannomatosis is a disease from the group of neurofibromatosis, manifested by the development of multiple schwannomas. Neuropathic pain is one of the main symptoms characteristic of peripheral schwannomas, however, the severity and prevalence of the pain syndrome does not always correlate with the location of the tumors. According to modern concepts, the key factors influencing the characteristics of the pain syndrome are the target gene and the type of pathogenic variant. The most severe widespread pain is observed in patients with pathogenic variants in the LZRT1 gene, while patients with mosaic variants may not even have local pain associated with tumors. Patients with variants in SMARCB1 may have no pain or localized pain that responds well to surgical treatment. Выявить особенности болевого синдрома у пациентов со шванномами в зависимости от генетической предрасположенности. В исследование включены 46 пациентов с периферическими, спинальными и интракраниальными шванномами, соответствующие фенотипу шванноматозов согласно клиническим критериям 2022 г. Всем пациентам проводилось секвенирование генов LZRT1, Nf2 и SMARCB1 и исследование количества копий в гене NF2. Наиболее тяжелая распространенная боль отмечалась у пациентов с патогенными вариантами в гене LZRT1, при этом у пациентов с мозаичными вариантами могло не быть даже локальной боли, связанной с новообразованиями. У пациентов с вариантами в SMARCB1 могло не быть боли или выявлялась локальная боль, хорошо реагирующая на хирургическое лечение. Дальнейшие исследования молекулярных особенностей шванноматозов и драйверных мутаций в патогенезе боли необходимы для повышения эффективности терапии боли в данной группе пациентов.
antibodies
2026-02-27 | Deciphering and Targeting the Schwannoma-Neuron-Macrophage Crosstalk for the Treatment of Schwannomatosis and Associated Pain.
Non-NF2 Schwannomatosis (SWN) is a genetic disorder characterized by multiple non-malignant schwannomas growing on the spine and peripheral nerves. Patients with SWN overwhelmingly present with intractable chronic pain. There are no FDA-approved drugs to halt tumor growth or alleviate pain. Research on SWN is hindered by the lack of clinically relevant models. We established patient-derived SWN cell lines from patients with varying pain levels and developed orthotopic patient-derived xenograft models that reproduce patients' pain responses. We further developed a novel dorsal root ganglia (DRG) imaging model for longitudinal intravital imaging of macrophage infiltration into the DRG and sensory neuron pain response. Leveraging these novel models, we found that Schwannomas grown distantly in the peripheral nerve caused an influx of macrophages into the DRG. These macrophages in the DRG caused pain via overproducing IL-6. Treatment with anti-IL-6 antibody reduced pain but had modest efficacy in tumor control. We identified epidermal growth factor receptor (EGFR) signaling as a key driver of schwannoma growth and an escape mechanism from anti-IL6 treatment. Finally, we found that combining IL-6 and EGFR blockade effectively controlled pain and tumor growth simultaneously in SWN models. In summary, we elucidated the cellular and molecular crosstalk between schwannoma (HMGB1), neuron (CCL2), and macrophage (IL-6) in driving pain, and identified the EGF signaling pathway as a driver of SWN tumor progression, thereby uncovering novel therapeutic targets that may improve clinical management of SWN.
2026-02-16 | A cochlea-sparing strategy for non-invasive control of intracranial schwannomas via peripheral irradiation and anti-PD-1 therapy enhanced by STING activation.
Rationale: NF2-related schwannomatosis (NF2-SWN) is a progressive neurological disorder with a hallmark of bilateral vestibular schwannomas (VSs), leading to irreversible hearing loss and reduced quality of life. To date, the FDA has not approved any pharmacological therapies for treating VS or hearing loss. While radiotherapy (RT) is the standard treatment for growing VSs, it often exacerbates hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their efficacy in non-malignant tumors like VS remains largely unexamined. Methods: We used immune-competent VS mouse models to assess the efficacy of combined anti-PD1 (αPD1) and RT treatment, tumor growth, and hearing preservation. Results: We found three significant therapeutic benefits: i) RT induces immunogenic cell death and activates the STING pathway, enhancing αPD1 efficacy and generating long-term immune memory, ii) The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) RT to peripheral nerve tumor induces a systemic abscopal effect, which enhances αPD-1 efficacy to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. Conclusion: Our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and NF2-SWN.
2026-02-12 | NKG2D upregulation sensitizes tumors to combined anti-PD1 and anti-VEGF therapy and prevents hearing loss.
NF2-related schwannomatosis (NF2-SWN) is a debilitating condition, characterized by bilateral vestibular schwannomas (VSs) that progressively cause irreversible sensorineural hearing loss. Current management relies on surgery or radiotherapy, while bevacizumab (αVEGF) is used off-label, with variable and often transient efficacy. Effective therapies that durably suppress tumor growth and preserve hearing are urgently needed. Although immune checkpoint inhibitors have transformed cancer treatment, their efficacy in non-malignant tumors such as VS remains unclear. Here, we evaluate combined anti-PD1 (αPD1) and αVEGF therapy in two syngeneic, immune-competent VS models. Combination treatment significantly outperforms either monotherapy, inhibiting tumor growth and preventing hearing loss. Mechanistically, αVEGF enhances αPD1 efficacy by normalizing tumor vasculature, improving drug delivery and immune cell infiltration, and promoting cytotoxicity of T and NK cells via NKG2D upregulation. Combined treatment effectively controls tumor growth that progresses despite anti-VEGF therapy. These findings support αPD1 and αVEGF combination therapy as a promising strategy for NF2-SWN.
2025-10-01 | P14.18.A SCHWANNOMAS DISPLAY CONSERVED CELLULAR STATES AND PREFERENTIAL MHC CLASS II ANTIGEN PRESENTATION ACROSS DIFFERENT GENETIC BACKGROUNDS AND ANATOMIC LOCATIONS
Abstract BACKGROUND Despite being associated with molecular alterations in the NF2 gene, there is limited understanding of the gene expression programs that govern the behavior of schwannomas—both in sporadic cases and in patients with schwannoma predisposition syndromes—and how these programs relate to tumor anatomic location. MATERIAL AND METHODS We characterized the transcriptional heterogeneity of schwannomas across different genetic backgrounds and anatomic locations at single-cell resolution. Tumor samples from patients undergoing resection for symptomatic schwannoma were dissociated and processed for whole-transcriptome profiling using Smart-seq2. Our cohort included 22 schwannomas: 5 from schwannomatosis patients, 11 from neurofibromatosis type 2 (NF2) patients, and 6 sporadic tumors (3 post-radiation). Anatomically, 12 tumors were from cranial nerves (11 vestibular, 1 accessory), and 10 from spinal or peripheral nerves. RESULTS We profiled 11,373 cells, including 4,725 neoplastic cells and various non-neoplastic populations. Copy number alteration analysis revealed intratumoral polyclonality. Non-negative matrix factorization identified six conserved transcriptional metaprograms related to stress response, myelin production, antigen presentation, interferon signaling, glycolysis, and extracellular matrix remodeling. Notably, schwannomas exhibited a distinctive antigen presentation metaprogram, enriched for MHC class II genes (e.g., HLA-DRA, HLA-DRB1). Additionally, we observed a distinct interferon signaling program, which was conserved across most tumors but attenuated in vestibular schwannomas, indicating a potential mechanism of regional immune evasion. Comparison with pan-cancer data confirmed the relative uniqueness of these immune-related programs to schwannomas. CONCLUSION We provide a comprehensive single-cell transcriptomic analysis of schwannomas across genetic and anatomic contexts. Our findings reveal unique, conserved immune-related transcriptional programs, particularly involving antigen presentation and interferon signaling, which may contribute to tumor immune evasion and inform future immunotherapeutic strategies.
2025-09-22 | Focused ultrasound-mediated drug delivery of bevacizumab in treating NF2-related schwannomatosis in an animal model
Neurofibromatosis type 2 (NF2)-related schwannomatosis is an autosomal dominant genetic disorder characterized by the development of cranial and peripheral nerve schwannomas, including bilateral vestibular schwannomas and dorsal root ganglion schwannomas along the spinal axis, both of which are associated with substantial morbidity. Current therapeutic strategies comprise surgical resection, radiotherapy, and systemic administration of bevacizumab; however, these approaches are frequently limited by high recurrence rates and morbidity. In this study, a transgenic murine model (Postn-Cre;Nf2flox/flox) was employed to investigate the combined effect of intraperitoneally administered human bevacizumab (5 mg/kg b. w.) and focused ultrasound (FUS) on drug delivery and tumor growth in DRG schwannomas. ELISA-based analysis demonstrated a 2.88-fold increase in intratumoral bevacizumab concentration following the combined application of human bevacizumab and FUS, compared to bevacizumab alone. Tumor growth was assessed using 7-tesla MRI of the spine with intravenous gadolinium contrast, and outcomes were compared across five experimental groups: 1) human bevacizumab alone, 2) murine bevacizumab alone, 3) human bevacizumab combined with FUS, 4) FUS alone, and 5) untreated controls. Treatments, including drug administration and FUS exposure, were performed three times at two-week intervals. Notably, the combined treatment group (human bevacizumab + FUS) exhibited a trend toward tumor size reduction.
gene therapies
2026-03-24 | Malignant peripheral nerve sheath tumors arising in SMARCB1-associated schwannomatosis: illustrative cases.
Schwannomatosis is a rare tumor predisposition syndrome characterized by benign peripheral nerve sheath tumors in the absence of bilateral vestibular schwannomas. In rare cases, malignant peripheral nerve sheath tumors (MPNSTs) may arise with schwannomatosis, particularly with SMARCB1 mutations. These malignancies pose significant diagnostic and therapeutic challenges and a poor prognosis. The authors present 2 cases of high-grade MPNST with SMARCB1-associated schwannomatosis. Both presented with rapidly enlarging and concerning imaging features, including heterogeneous enhancement, central necrosis, and low apparent diffusion coefficient values. Histopathological analysis confirmed high-grade MPNST with elevated mitotic activity and loss of H3K27me3. Both patients underwent en bloc resection with negative margins. One patient remains disease free at 5 years; the other patient developed metastatic recurrence and died. A systematic review identified 20 cases in the literature. These cases emphasize clinical vigilance for malignant transformation in schwannomatosis, particularly with rapidly enlarging lesions or new neurological symptoms. MRI and FDG-PET can aid in identifying concerning features. Despite margin-negative resection, recurrence and metastasis may occur, reflecting the tumor's aggressive biology. Genetic counseling may be considered in SMARCB1-associated cases. While malignant transformation is much more common in NF1 lesions, rare cases do arise in schwannomatosis, requiring close surveillance and multidisciplinary management. https://thejns.org/doi/10.3171/CASE25610.
2026-01-22 | [Schwannomatosis diagnosed from an approximately 30-year history of multiple mononeuropathy accompanied by multiple cauda equina nodules: a case report].
A 51-year-old woman presented with left drop foot at age 20, numbness in the right fourth and fifth fingers at age 45, and numbness in both lower extremities at age 51. Lumbar MRI revealed multiple cauda equina nodules, while ultrasonography of the peripheral nerve identified enlarged nerve bundles in several locations, including the right ulnar and left peroneal nerves. Nerve conduction studies and upper extremity MRI findings were consistent with these observations, and head MRI confirmed the absence of auditory schwannomas. Schwannomatosis (SWN) is a rare disease characterized by the formation of multiple peripheral schwannomas, associated with genetic abnormalities such as SMARCB1 and LZTR1. When multiple peripheral nerve tumors are detected, SWN should be considered as part of the differential diagnosis.
2026-01-12 | Central nervous system schwannoma, VGLL-fused (EWSR1::VGLL1 fusion) with neuroblastoma-like cell dense areas in the frontal lobe of a young man with schwannomatosis due to a germline LZTR1 mutation.
We report a central nervous system schwannoma, VGLL-fused in a young man's frontal lobe. Somatic abnormalities included an EWSR1::VGLL1 fusion, which incorporated the entire translated region of VGLL1, but excluded most domains of EWSR1. The tumor histologically merged with the brain, and showed both schwannoma-like and neuroblastoma-like areas. A germline LZTR1 mutation was subsequently identified, implying the patient suffered from schwannomatosis.
2025-08-12 | SMARCB1-related schwannomatosis and other SMARCB1-associated phenotypes: clinical spectrum and molecular pathogenesis.
SMARCB1 is a core unit of the BAF chromatin remodelling complex and its functional impairment interferes with the self-renewal and pluripotency of stem cells, lineage commitment, cellular identity and differentiation. SMARCB1 is also an important tumour suppressor gene and somatic SMARCB1 pathogenic variants (PVs) have been detected in ~ 5% of all human cancers. Additionally, germline SMARCB1 PVs have been identified in patients with conditions as clinically diverse as Rhabdoid Tumour Predisposition Syndrome type 1 (RTPS1), schwannomatosis and neurodevelopmental disorders such as Coffin-Siris syndrome (CSS). RTPS1 is characterized by the occurrence of highly malignant atypical teratoid rhabdoid tumours (AT/RT) affecting mostly infants, whereas SMARCB1-related schwannomatosis is generally diagnosed after the age of 30 and is characterized by benign schwannomas. Patients with germline SMARCB1 PVs and neurodevelopmental disorders do not usually develop SMARCB1-deficient tumours but instead exhibit severe intellectual disability and congenital malformations. It is intriguing how germline SMARCB1 PVs can be responsible for these very different pathologies. However, a network of different factors has emerged that play important roles in this context. Thus, the tumour phenotype associated with germline SMARCB1 PVs is determined by the nature and location of the SMARCB1 mutation and the timing of SMARCB1 inactivation in specific progenitor cells. Biallelic complete loss of SMARCB1 function during a narrow time window of early embryonic development in neural crest cells is essential for AT/RT development. By contrast, hypomorphic SMARCB1 PVs during later developmental stages affecting more differentiated Schwann cell precursors give rise to schwannomas. However, the loss of the wild-type SMARCB1 allele is insufficient for schwannoma growth which appears to be dependent upon concomitant somatic NF2 PVs in patients with SMARCB1-related schwannomatosis according to the four-hit/three-step model of tumorigenesis. In patients with neurodevelopmental disorders such as CSS, germline PVs would appear to cluster within the C-terminal SMARCB1 domain, interfering with the nucleosomal interactions of SMARCB1 but not with its tumour suppressor activity.
2025-03-07 | Genetic Basis and Clinical Management of Schwannomatosis.
Schwannomatosis (SWN) is now recognized as a broad classification that includes neurofibromatosis (NF) type 2, reflecting their shared genetic and phenotypic characteristics. Previously, SWN and NF type 2 were considered distinct clinical entities; however, the 2022 classification revision has unified them under the umbrella of SWN, with NF type 2 now referred to as NF2-related SWN. SWN arises from mutations in NF2, SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) or LZTR1 (leucine zipper like transcription regulator 1). Recent diagnostic criteria for SWN incorporate molecular classification, including "NF2-related SWN", "SMARCB1-related SWN", "LZTR1-related SWN", "22q-related SWN", "SWN-not otherwise specified", or "SWN-not elsewhere classified". NF2-related SWN is a genetic condition where all individuals with a germline or constitutional NF2 mutation are destined to develop the disease. The pathogenesis of SMARCB1- or LZTR1-related SWN follows a three-step, four-hit model. This involves retention of the mutated germline SMARCB1 or LZTR1 allele in the tumor, loss of the wild-type chromosome 22, and somatic mutation in the NF2 gene. Clinically, NF2-related SWN involves bilateral vestibular schwannomas, with treatment options including microsurgery, radiotherapy, and bevacizumab, each with specific benefits and limitations. Patients with SWN frequently present with chronic pain caused by schwannomas, which often does not correlate with tumor size, location, or burden. Management of SWN is primarily symptom-based. Surgical intervention is reserved for symptomatic lesions, particularly in cases of spinal cord compression or significant functional impairments. Multidisciplinary approaches to pain management are critical for enhancing quality of life. Although malignant transformation of schwannomas is a potential risk, the life expectancy of individuals with SWN is nearly normal. Despite advancements in understanding SWN, further research is necessary to elucidate the underlying genetic mechanisms and to develop targeted therapeutic strategies for this complex disorder.
small molecules
2026-07-15 | Addition of Losartan to Immune Checkpoint Blockade Improves Tumor Control and Neurological Outcomes in Models of NF2-Related Schwannomatosis
NF2 -related schwannomatosis ( NF2 -SWN) is a devastating genetic disorder characterized by the development of bilateral vestibular schwannomas (VSs), which are histologically benign tumors that cause hearing loss and vestibular dysfunction. Currently, there are no FDA-approved pharmacologic therapies for VS or VS-associated hearing loss, representing a major unmet medical need for patients with NF2 -SWN. Although immunotherapy has transformed the treatment of many solid malignancies, its efficacy in VS has not been comprehensively evaluated. We employed VS mouse models that faithfully recapitulate tumor-induced hearing loss and ataxia to evaluate the therapeutic efficacy of anti-PD-1 (αPD-1) immunotherapy alone and in combination with losartan, an angiotensin II type 1 receptor blocker known to reduce tumor extracellular matrix density and normalize tumor vascular perfusion. Tumor growth, survival, hearing function, and neurological outcomes were assessed. Losartan significantly enhanced the intratumoral delivery of αPD-1 antibody and increased immune effector cell infiltration in VS. Consequently, combined losartan and αPD-1 therapy more effectively inhibited tumor growth and prolonged survival compared with monotherapy. In parallel, losartan attenuated inflammatory signaling, thereby reducing neuro-edema. As a result, the combination treatment more effectively prevented tumor-induced hearing loss and alleviated ataxia in the VS mouse model. Targeting the fibrotic tumor microenvironment with losartan sensitizes vestibular schwannomas to immunotherapy and improves neurological outcomes. These findings provide critical preclinical evidence supporting a novel combination strategy using ICIs for NF2 -SWN and offer important insights for the design of future clinical trials aimed at suppressing VS growth while preserving hearing and neurological function.
2026-05-29 | Comprehensive characterization of spinal ependymomas in NF2-Schwannomatosis.
Spinal ependymomas (SE) account for 10% of ependymomas and are the most frequent spinal glial tumors. NF2-related Schwannomatosis (NF2-SWN) patients are predisposed to multiple SE in addition to other tumors, schwannomas and meningiomas. Surgery remains the main treatment option, but mays lead to severe morbidity. In many cases, it is the cystic rather than the solid component of the tumor that drives neurological symptoms and ultimately necessitates surgical intervention. Understanding tumor and associated cyst formation is therefore important to develop new therapeutic approaches. This clinical and radiological study includes 33 NF2-SWN with a long-term follow-up and 11 sporadic SE patients. Tumor and cyst characteristics were assessed, and histopathological analyses performed, including multiplex immunohistochemistry and RNA sequencing. Radiological analysis revealed that peritumoral edema frequently precedes cystic formation. Histological analysis showed that macrophage infiltration, particularly by SPP1-positive macrophages, was associated with cystic growth in NF2-SWN SE. RNAseq analysis identified distinct immune microenvironments differentiating NF2-SWN from sporadic SE, including differences in VEGF-C expression. Consistent with these results, AXITINIB, a selective inhibitor of VEGFR and VEGFR3 which acts as the receptor for VEGF-C, was proposed to a NF2-SWN patient with a progressing cystic SE and resulted in clinical improvement accompanied by a reduction in the peritumoral cyst. These results support a role for VEGF signaling and macrophage-mediated microenvironmental changes in edema and cystic growth of NF2-SWN SE. The observed clinical response to AXITINIB in an index patient suggests that new combinations of anti-angiogenic therapies may represent a promising early targeted approach.
2026-05-13 | TEAD inhibitors synergize with MEK, SHP2 and mTOR inhibitors in NF1 and NF2 cell lines.
Neurofibromatosis type 1 (NF1) and NF2 -related Schwannomatosis ( NF2 -SWN) are both inherited syndromes characterized by Schwann cell tumors. NF1 tumors harbor activated Ras/MEK/ERK, while NF2 -SWN tumors harbor activated mechanosignaling pathways, including Hippo/YAP-TAZ/TEAD. To test combinatorial strategies in tumor cell lines, we first screened a new-generation TEAD inhibitor, VT103, against 123 drugs and then validated the hits with pairwise titrations. VT103 consistently synergized with inhibitors of MEK (trametinib and selumetinib), SHP2 (TNO155) and mTOR (everolimus). The highest synergy ZIP score, calculated using SynergyFinder, was ~65 in the NF2 -SWN cell line SC4, with lower magnitudes in an NF1 cell line.
2026-04-03 | Quantitative imaging of schwannoma captures heterogeneity and accelerates preclinical testing, revealing distinct impacts of targeted therapies.
Schwannomas are debilitating hallmarks of familial schwannomatoses and common sporadic tumors that form on spinal and cranial nerves. Drug-based therapies for schwannoma are desperately needed but their development has been extremely slow and disappointing, impeded particularly by the poorly understood and surprisingly complex and heterogeneous biology of schwannomas, and by the inefficient use of physiologically relevant in vivo preclinical models. We have addressed these gaps by developing a quantitative imaging-centered workflow that allows both a deep analysis of schwannoma development and accelerated preclinical testing in a widely used genetically engineered mouse model of neurofibromatosis type 2-related schwannomatosis (NF2-SWN). We deployed our workflow to study schwannoma development and to test two clinically relevant drugs (rapamycin and brigatinib) head-to-head. Our results uncovered the very early onset of heterogeneity and macrophage recruitment to initiating schwannomas, and the unexpectedly distinct impacts of the two drugs on both, highlighting the value of the pipeline for rapid, innovative future drug-testing.
2026-03-26 | Recurrent Epidermal Growth Factor Receptor 2 (ERBB2) Mutations Drive the Pathogenesis of Multifocal Neurofibroma Variants.
Recurrent Epidermal Growth Factor Receptor 2 (ERBB2) mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by 2 cases of plexiform neurofibromas harboring ERBB2 hotspot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA-sequencing panel. Clinical history, radiologic findings, and follow-up information were retrieved from chart review. Pathologic features, and genomic and germline findings, were reviewed. We identified 5 patients; all except 1 were women, with a median age of 34 years (range: 24-40 years). All revealed multiple PNSTs with a segmental distribution on imaging, including the pelvis (n = 2), upper limb (n = 2), and stomach (n = 1). None of the patients had a family history or displayed clinical features of neurofibromatosis type 1, except for 1 patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n = 4), intraneural with Schwann cell micronodule (n = 2), and diffuse (n = 1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n = 3; exon 20, n = 2; exon 21, n = 1). One additional case had 2 concurrent ERBB2 mutations in exons 20 and 21. On germline testing, only 1 patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, and LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation, 1 being enrolled on an HER2 inhibitor trial for 7 years owing to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications.
cell therapies
2026-08-10 | Deletion of the Salmonella pathogenicity island 2 gene, spiC, in attenuated Salmonella Typhimurium VNP20009 optimizes its potential for bacterial schwannoma therapy.
Recent advances in systems biology and immunotherapy have spurred the use of bacteria as therapeutic vehicles for cancer treatment. Currently, Bacillus Calmette-Guérin remains the only FDA-approved bacterial strain for high-risk, non-muscle-invasive bladder cancer. Although safety concerns have been raised, attenuated Salmonella Typhimurium strains such as VNP20009 have advanced to clinical trials targeting fast-growing human tumors. Notably, this strain induces robust immunological control of slow-growing tumors such as NF2-related schwannomatosis (NF2-SWN) in preclinical murine models. Here, we genetically characterize VNP20009 with the goal of constructing genetically defined attenuated strains that retain its promising therapeutic features while improving safety. Specifically, we investigated the contribution of the Salmonella pathogenicity island I (SPI-1) and SPI-2 type III secretion systems to antitumor efficacy and biosafety. Mutation of the SPI-1 gene sipB, a key structural component required for SPI-1 type III secretion system function, partially reduced tumor control in NF2-SWN murine schwannoma models, suggesting that bacterial invasion alone does not fully account for antitumor activity. In contrast, deletion of the SPI-2 gene spiC, a key effector required for intracellular survival, preserved robust tumor regression in NF2-SWN murine schwannoma models while improving safety and reducing systemic toxicity. To create a genetically defined and tractable platform, we generated two attenuated strains-AST101 and AST101-ΔspiC-which retain key mutations present in VNP20009 but lack ill-characterized background mutations. In the syngeneic NF2-SWN mouse schwannoma model, both strains significantly suppressed tumor growth compared to PBS. Collectively, these findings support the development of rationally engineered Salmonella Typhimurium strains with enhanced safety and preserved antitumor efficacy. Given long-standing safety concerns surrounding the therapeutic use of live bacteria, we constructed a ΔspiC mutant of VNP20009 and demonstrated that it provides a markedly improved safety profile while retaining antitumor efficacy in NF2-related schwannomatosis mouse schwannoma models. In addition, we created two genetically defined Salmonella Typhimurium strains, AST01 and AST01-ΔspiC, which incorporate the key-targeted mutations found in VNP20009 and VNP20009-ΔspiC, respectively. These engineered strains offer a well-defined genetic background, enabling precise investigation of the bacterial traits responsible for Salmonella Typhimurium-mediated tumor control and thus further improvement of attenuated strains optimized for bacteriotherapy of neoplasms.
2025-03-03 | Development of CAR-T cell therapy for NF1/SWN-related nerve sheath tumor treatment.
Neurofibromatosis type 1 (NF1) and schwannomatosis (SWN) are rare genetic disorders with distinct genetic etiologies. Both syndromes are predominantly characterized by the development of multiple benign nerve sheath tumors, which typically arise from cranial/peripheral nerves. The management of NF1/SWN-associated benign nerve sheath tumors pose a substantial clinical challenge. In recent years, immunotherapy has demonstrated significant efficacy in treating various tumors, but its application to NF1/SWN has not been explored. In this study, we first evaluated the feasibility of chimeric antigen receptor (CAR)-T cell therapy for the treatment of benign NF1/SWN-related nerve sheath tumor by analyzing the expression of multiple antigens in 85 tumor samples. Our findings revealed that epidermal growth factor receptor (EGFR/HER1) was highly expressed in most samples, indicating its potential as an ideal target for CAR-T cell therapy. Additionally, TGFβ1 and PDL1, key inhibitory regulators of T cell function within solid tumor microenvironment (TME), were universally overexpressed in these samples, highlighting the immunosuppressive nature of NF1/SWN tumors. To target HER1, we constructed CARs using three distinct scFvs (806, E2 and NEC). All three types of CAR-T cells demonstrated significant tumor-eliminating capability against NF1/SWN tumor cell lines, with 806 CAR-T cells showing the highest efficacy. Considering the immunosuppressive TME, we knocked out TGFBR2 and/or PDCD1 in 806 CAR-T cells using CRISPR/Cas9. Their anti-tumor efficacy was further evaluated using a 3D tumor spheroid model, and the gene-edited 806 CAR-T cells exhibited superior anti-tumor efficacy. In conclusion, we identified HER1 as a target for CAR-T cell therapy in NF1/SWN-related nerve sheath tumors, and developed anti-HER1 CAR-T cells that effectively eliminated NF1/SWN tumor cells, providing a promising therapeutic strategy for patients with these conditions.
2023-01-01 | Allograft nerve repair to prevent sensorimotor loss after nerve sheath tumor resection
Acellularized nerve allografts (ANAs) have been developed as substitutes for nerve autograft to promote nerve regeneration after surgical repair. In this video, the authors demonstrate operative techniques for using ANAs to repair potentially functional nerve fascicles during tumor resection. A 67-year-old female with schwannomatosis requested resection of a painful enlarging mass of the left ulnar nerve proximal to the elbow. During surgery, neuromonitoring suggested that fascicles entering the tumor could be functional. Therefore, nerve allograft was used to repair the transected fascicles. The patient recovered with full strength and sensation in the ulnar distribution, with resolution of her preoperative symptoms. The video can be found here: https://stream.cadmore.media/r10.3171/2022.10.FOCVID22101.
2021-09-14 | Schwann cell‐derived exosomes: Janus‐faced mediators of regeneration and disease
The phenotypic plasticity of Schwann cells (SCs) has contributed to the regenerative potential of the peripheral nervous system (PNS), but also pathological processes. This double-sided effect has led to an increasing attention to the role of extracellular vesicles (EVs) or exosomes in SCs to examine the intercellular communication between SCs and their surroundings. Here, we first describe the current knowledge of SC and EV biology, which forms the basis for the updates on advances in SC-derived exosomes research. We seek to explore in-depth the exosome-mediated molecular mechanisms involved in the regulation of SCs and their microenvironment. This review concludes with potential applications of SC-derived exosomes as delivery vehicles for therapeutics and biomarkers. The goal of this review is to emphasize the crucial role of SC-derived exosomes in the functional integration of the PNS, highlighting an emerging area in which there is much to explore and re-explore.
other
2025-11-14 | NF2 lacking exon 11 induced by antisense gene therapy is able to partially recover merlin deficiency on NF2 -SWN iPSC-derived spheroid model
Abstract NF2 -related Schwannomatosis ( NF2 -SWN) is an inherited autosomal dominant disorder resulting from loss-of-function mutations in the NF2 gene, for which no effective treatment is currently available. Furthermore, truncating variants in NF2 are associated with the severest phenotype compared to in-frame or missense variants. Previously, a shorter NF2 isoform with exon 11 skipped (merlin_e-11), induced through antisense morpholino oligomers (PMOs), was able to partially rescue the deleterious effect of nonsense variants located at that exon in patients’ primary fibroblast. To test the potential of this approach into Schwann cells, those responsible of NF2 -SWN tumours, we developed an iPSC-based model carrying heterozygous and homozygous truncating variants on exon 11 of the NF2 gene and differentiated them to Schwann cells forming spheroids. After 3 days of treatment, merlin_e-11 expression was induced in NF2-deficient cell lines. Furthermore, key pathways associated with NF2-deficiency in schwannomas, such as PI3K/Akt/mTORC and YAP levels, were recovered without signs of toxicity. These results confirm that the PMO treatment induces effective skipping of exon 11 in Schwann cell spheroids, generating an hypomorphic merlin_e-11 that has the capacity to partially rescue merlin-deficiency in NF2 -SWN spheroid cell model and it being a potential treatment of patients harbouring truncating variants located in exon 11.
2024-06-17 | [Features of course of pain syndrome in patients with schwannomatosis].
To identify the characteristics of pain syndrome in patients with schwannomas depending on genetic predisposition. The study included 46 patients with peripheral, spinal and intracranial schwannomas, corresponding to the schwannomatosis phenotype according to the 2022 clinical criteria. All patients underwent sequencing of the LZRT1, Nf2 and SMARCB1 and a copy number study in the NF2. The most severe widespread pain was observed in patients with pathogenic LZRT1 variants, while patients with mosaic variants may not even have local tumor-related pain. Patients with SMARCB1variants may have no pain or have localized pain that responds well to surgical treatment. Further studies of the molecular features of schwannomatosis and driver mutations in the pathogenesis of pain are necessary to improve the effectiveness of pain therapy in this group of patients. Schwannomatosis is a disease from the group of neurofibromatosis, manifested by the development of multiple schwannomas. Neuropathic pain is one of the main symptoms characteristic of peripheral schwannomas, however, the severity and prevalence of the pain syndrome does not always correlate with the location of the tumors. According to modern concepts, the key factors influencing the characteristics of the pain syndrome are the target gene and the type of pathogenic variant. The most severe widespread pain is observed in patients with pathogenic variants in the LZRT1 gene, while patients with mosaic variants may not even have local pain associated with tumors. Patients with variants in SMARCB1 may have no pain or localized pain that responds well to surgical treatment. Выявить особенности болевого синдрома у пациентов со шванномами в зависимости от генетической предрасположенности. В исследование включены 46 пациентов с периферическими, спинальными и интракраниальными шванномами, соответствующие фенотипу шванноматозов согласно клиническим критериям 2022 г. Всем пациентам проводилось секвенирование генов LZRT1, Nf2 и SMARCB1 и исследование количества копий в гене NF2. Наиболее тяжелая распространенная боль отмечалась у пациентов с патогенными вариантами в гене LZRT1, при этом у пациентов с мозаичными вариантами могло не быть даже локальной боли, связанной с новообразованиями. У пациентов с вариантами в SMARCB1 могло не быть боли или выявлялась локальная боль, хорошо реагирующая на хирургическое лечение. Дальнейшие исследования молекулярных особенностей шванноматозов и драйверных мутаций в патогенезе боли необходимы для повышения эффективности терапии боли в данной группе пациентов.
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Drug Discovery Landscape
1 orphan drug designation for Full schwannomatosis.
1 orphan drug designation for Full schwannomatosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
N-Hydroxy-4-(3-methyl-2-(S)phenyl-butyrylamino)benzamide | small molecules | FDA | 2012-01-13 | — | Recursion Pharmaceuticals Inc. |
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