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Background <p>Although most vestibular schwannomas (VS) occur sporadically, both sporadic and hereditary tumors share common molecular features beyond the loss of <i>NF2</i>. New evidence highlights the role of interconnected signaling pathways and epigenetic regulation in Schwann cell tumorigenesis, pointing toward potential molecularly targeted therapeutic strategies.</p> Methods <p>This review synthesizes preclinical, molecular, and clinical evidence to examine genetic and epigenetic mechanisms underlying VS, therapeutic strategies, and contributors to hearing loss. A structured search of ClinicalTrials.gov identified 21 Phase 1–3 interventional therapeutic trials.</p> Results <p>VS pathogenesis is driven by <i>NF2</i> loss and merlin deficiency, leading to dysregulation of Hippo/YAP-TAZ, PI3K/AKT/mTOR, VEGF, MAPK, and adhesion pathways. Epigenetic alterations, including DNA methylation, chromatin remodeling, non-coding RNAs, and SOX10 dysfunction, further shape tumor behavior. Clinical trial analysis revealed a predominance of early-phase, non-comparative studies, limited progression to later-phase trials, and incomplete results reporting, indicating gaps in high-quality evidence. Bevacizumab remains the most consistent systemic therapy for select <i>NF2</i>-related cases, while other agents such as icotinib, lapatinib, everolimus, selumetinib, and brigatinib have shown modest activity, primarily disease stabilization. Emerging approaches, including TEAD inhibition, PI3K/mTOR blockade, MEK inhibition, and combined signaling-epigenetic strategies, show preclinical promise. Hearing loss is multifactorial, involving tumor-secreted factors, inflammation, vascular changes, and inner ear damage alongside nerve compression.</p> Conclusion <p>VS biology reflects integrated genetic and epigenomic dysregulation. Advancing care will require multi-omic classification, biomarker-driven trials, and combination therapies targeting both signaling and epigenetic vulnerabilities. Future management is expected to shift toward personalized, mechanism-based strategies aimed at durable tumor control while preserving hearing and quality of life.</p>

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Vestibular schwannoma: genetic and epigenetic mechanisms, hearing loss, and emerging therapies

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月16日

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  • Franciska Otaner,
  • Vratko Himic,
  • Luis O. Vargas,
  • Matthew Abikenari,
  • Neelesh Pandey,
  • Shayndhan Sivanathan,
  • Olivia Kalmanson,
  • Aparna Govindan,
  • Diane Jung,
  • Dagoberto Estevez-Ordonez,
  • Amy Wang,
  • Sanjeeva Jeyaretna,
  • Ashish H. Shah,
  • Ricardo J. Komotar,
  • Bradley Gampel,
  • Christine Dinh,
  • Michael E. Ivan

摘要

Background

Although most vestibular schwannomas (VS) occur sporadically, both sporadic and hereditary tumors share common molecular features beyond the loss of NF2. New evidence highlights the role of interconnected signaling pathways and epigenetic regulation in Schwann cell tumorigenesis, pointing toward potential molecularly targeted therapeutic strategies.

Methods

This review synthesizes preclinical, molecular, and clinical evidence to examine genetic and epigenetic mechanisms underlying VS, therapeutic strategies, and contributors to hearing loss. A structured search of ClinicalTrials.gov identified 21 Phase 1–3 interventional therapeutic trials.

Results

VS pathogenesis is driven by NF2 loss and merlin deficiency, leading to dysregulation of Hippo/YAP-TAZ, PI3K/AKT/mTOR, VEGF, MAPK, and adhesion pathways. Epigenetic alterations, including DNA methylation, chromatin remodeling, non-coding RNAs, and SOX10 dysfunction, further shape tumor behavior. Clinical trial analysis revealed a predominance of early-phase, non-comparative studies, limited progression to later-phase trials, and incomplete results reporting, indicating gaps in high-quality evidence. Bevacizumab remains the most consistent systemic therapy for select NF2-related cases, while other agents such as icotinib, lapatinib, everolimus, selumetinib, and brigatinib have shown modest activity, primarily disease stabilization. Emerging approaches, including TEAD inhibition, PI3K/mTOR blockade, MEK inhibition, and combined signaling-epigenetic strategies, show preclinical promise. Hearing loss is multifactorial, involving tumor-secreted factors, inflammation, vascular changes, and inner ear damage alongside nerve compression.

Conclusion

VS biology reflects integrated genetic and epigenomic dysregulation. Advancing care will require multi-omic classification, biomarker-driven trials, and combination therapies targeting both signaling and epigenetic vulnerabilities. Future management is expected to shift toward personalized, mechanism-based strategies aimed at durable tumor control while preserving hearing and quality of life.