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Background <p>Neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome driven by mutations in the NF2 gene. The mutation leads to aberrant proliferation of Schwann cells along the vestibular division of cranial nerve VIII, resulting in bilateral vestibular schwannomas (VS) that cause progressive hearing loss and neurological dysfunction. Loss of the tumor suppressor merlin results in dysregulation of multiple oncogenic pathways, including VEGF, MAPK/ERK, PI3K/AKT/mTOR, EGFR/ErbB, PDGFR, and Hippo-YAP. The inability of conventional management modalities to address the multifocal and progressive nature of NF2-associated tumors has driven investigation into targeted therapies.</p> Methods <p>This review summarizes the evolving landscape of targeted therapies in NF2-associated vestibular schwannomas. Management of NF2-VS is individualized, with active surveillance favored for stable or smaller tumors, surgical resection pursued for symptomatic or enlarging lesions, and bevacizumab increasingly utilized as either a primary or adjunctive systemic option. Radiation therapy, by contrast, is employed selectively given its potential to compromise auditory function and its association with malignant transformation. Targeted agents such as bevacizumab (anti-VEGF), MEK inhibitors (selumetinib, trametinib), EGFR inhibitors (lapatinib, erlotinib), and mTOR inhibitors (everolimus) are examined across preclinical models and clinical trials. Emerging approaches including dual pathway inhibition and immunologic strategies such as VEGF receptor vaccination are also discussed. Importantly, NF2-VS exhibits molecular and clinical heterogeneity, with differing responses observed across pediatric and adult populations.</p> Conclusion <p>Therapeutic limitations of current targeted therapies include resistance, toxicity, and the modest efficacy of monotherapies. As such, future investigations must refine endpoints (e.g., hearing stabilization vs. tumor regression), optimize dosing strategies, and personalize therapy based on age, tumor biology, and clinical trajectory. This review highlights the translational challenges and opportunities that lie ahead in delivering clinically efficacious therapies specific to each patient.</p>

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A review of targeted therapies for NF2-related vestibular schwannoma: molecular pathogenesis, emerging therapeutics, and future clinical horizons

  • 期刊论文

  • 发表日期：

    2026年5月16日

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  • Morgan K. Sokol,
  • Joseph H. Ha,
  • Gordon Li,
  • Lily H. Kim

摘要

Background

Neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome driven by mutations in the NF2 gene. The mutation leads to aberrant proliferation of Schwann cells along the vestibular division of cranial nerve VIII, resulting in bilateral vestibular schwannomas (VS) that cause progressive hearing loss and neurological dysfunction. Loss of the tumor suppressor merlin results in dysregulation of multiple oncogenic pathways, including VEGF, MAPK/ERK, PI3K/AKT/mTOR, EGFR/ErbB, PDGFR, and Hippo-YAP. The inability of conventional management modalities to address the multifocal and progressive nature of NF2-associated tumors has driven investigation into targeted therapies.

Methods

This review summarizes the evolving landscape of targeted therapies in NF2-associated vestibular schwannomas. Management of NF2-VS is individualized, with active surveillance favored for stable or smaller tumors, surgical resection pursued for symptomatic or enlarging lesions, and bevacizumab increasingly utilized as either a primary or adjunctive systemic option. Radiation therapy, by contrast, is employed selectively given its potential to compromise auditory function and its association with malignant transformation. Targeted agents such as bevacizumab (anti-VEGF), MEK inhibitors (selumetinib, trametinib), EGFR inhibitors (lapatinib, erlotinib), and mTOR inhibitors (everolimus) are examined across preclinical models and clinical trials. Emerging approaches including dual pathway inhibition and immunologic strategies such as VEGF receptor vaccination are also discussed. Importantly, NF2-VS exhibits molecular and clinical heterogeneity, with differing responses observed across pediatric and adult populations.

Conclusion

Therapeutic limitations of current targeted therapies include resistance, toxicity, and the modest efficacy of monotherapies. As such, future investigations must refine endpoints (e.g., hearing stabilization vs. tumor regression), optimize dosing strategies, and personalize therapy based on age, tumor biology, and clinical trajectory. This review highlights the translational challenges and opportunities that lie ahead in delivering clinically efficacious therapies specific to each patient.