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:
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.
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.
2026-08-10 | 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.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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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