Targeted Therapies for Vestibular Schwannoma: Comparison
Please note this is a comparison between versions V2 by Sirius Huang and V1 by Ryota Tamura.

Vestibular schwannoma (VS) is a benign tumor that originates from Schwann cells in the vestibular component. Surgical treatment for VS has gradually declined over the past few decades, especially for small tumors. Gamma knife radiosurgery has become an accepted treatment for VS, with a high rate of tumor control. For neurofibromatosis type 2 (NF2)-associated VS resistant to radiotherapy, vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR)-targeted therapy (e.g., bevacizumab) may become the first-line therapy. Recently, aA clinical trial using a VEGFR1/2 peptide vaccine was also conducted in patients with progressive NF2-associated schwannomas, which was the first immunotherapeutic approach for NF2 patients. Targeted therapies for the gene product of SH3PXD2A-HTRA1 fusion may be effective for sporadic VS. Several protein kinase inhibitors could be supportive to prevent tumor progression because merlin inhibits signaling by tyrosine receptor kinases and the activation of downstream pathways, including the Ras/Raf/MEK/ERK and PI3K/Akt/mTORC1 pathways. Tumor-microenvironment-targeted therapy may be supportive for the mainstays of management. The tumor-associated macrophage is the major component of immunosuppressive cells in schwannomas. 

  • schwannoma
  • NF2
  • bevacizumab
  • VEGF
  • molecular targeted therapy

1. Introduction

Schwann cells originate from neural crest cells, which migrate with growing neurites during nerve development. Schwann cells, which form the myelin sheath of an axon, support neuronal function and regeneration [1].
Schwannoma (Sch) is one of the common benign intracranial tumors with an incidence of 1 per 100,000 [2]. Sch often presents between the ages of 40 and 60 years [2]. Among these cases, 80–90% originate from the vestibular nerve. About 5–10% of vestibular Schs (VSs) are observed as bilateral in neurofibromatosis 2 (NF2) patients. A total of 95% of NF2 patients show bilateral VSs [3]. About 60% of unilateral VSs and 90% of bilateral VSs show NF2 gene mutation and the dysfunction of its transcription product, moesin–ezrin–radixin-like (merlin) protein [4].
Currently, tThe mainstays of management are observation, surgery, and radiosurgery. Surgery with facial and auditory monitoring remains the only curative treatment for growing VSs of all sizes. Stereotactic radiosurgery is considered as a widely accepted treatment option for small-sized VSs. For larger tumors, combined treatment strategies are mostly recommended. In particular, gamma knife radiosurgery (GKRS) has become an accepted treatment for VS [5]. However, additional treatment is needed for some refractory cases. Tumor volume ≥15 cm3 is a significant factor predicting poor tumor control following GKRS [6]. There is no approved medical therapy for VS. For refractory VS with high risks of surgical treatment or GKRS, medical therapies that can slow tumor growth are urgently needed.

2. Inflammation and Stress Reaction

2.1. COX2

The expression of cyclooxygenase 2 (COX-2) is associated with sporadic and NF2-related VS proliferation. Mutations in the NF2 gene can activate the Hippo pathway, in which YAP can promote the transcription of COX-2 for prostaglandin production. Prostaglandin E2 (PGE2) catalyzed by COX-2 has multiple roles in cell proliferation, apoptosis, angiogenesis, inflammation, and immune monitoring. COX-2 inhibitors may have the potential to inhibit the growth of VS [64,65][7][8]. A negative correlation between aspirin users and sporadic VS growth has been demonstrated [66,67][9][10]. In addition to inhibiting COX-2, aspirin can also suppress the activated NF-κB pathway in VS, which may be another potential mechanism. However, other studies demonstrated that there is no growth inhibitory effect for celecoxib on NF2-related VS or aspirin on sporadic VS [66,67][9][10]. Other studies have shown that NSAIDs, glucocorticoids, and other immunosuppressive drugs could not alter the expression of COX-2 in sporadic Sch [68][11].

2.2. Hsp90

Heat shock protein 90 (HSP90) is a ubiquitous molecule. The absence of Hsp90 results in proteasomal degradation [69][12]. The dysregulation of the Hippo pathway is necessary for schwannomagenesis, and MAPK signaling acts as a modifier for Sch formation. Furthermore, the pharmacological co-inhibition of YAP/TAZ transcriptional activity and MAPK signaling shows a synergistic size reduction in a mouse Sch model [70][13]. In a recent study, a novel small-molecule inhibitor compound of HSP90, NXD30001 (pochoxime A), was able to show reduced growth of NF2-deficient tumors in vivo. There are no current clinical trials using an HSP90 inhibitor [71][14]. The molecular patterns and mutations described for VS are summarized in Table 1.
Table 1.
 Molecular patterns and mutations currently described for VS.

5. Ongoing Clinical Trials

Table 2 shows ongoing clinical trials using multimodal treatment strategies for Sch. The superselective intraarterial infusion of bevacizumab is performed to control tumor progression (NCT01083966). Because of the promising results found with bevacizumab, it may be safely used by direct intracranial superselective intraarterial infusion up to a dose of 10mg/kg in order to enhance survival and hearing function. Another six trials are using medical treatment strategies. Crizotinib, AR-42 (OSU-HDAC42), everolimus, selumetinib (MEK 1/2 inhibitor), and tanezumab (a monoclonal antibody against nerve growth factor as a treatment for pain) are being evaluated in the trials. A previous meta-analysis suggests that there is insufficient evidence to recommend aspirin usage in patients with VS [77,78][21][22]. High-quality trials are warranted to determine the efficacy of aspirin in reducing VS growth (NCT03079999).
Table 2.
 Active and recruiting clinical trials using medical therapeutic approaches for schwannoma.


  1. Jessen, K.R.; Mirsky, R.; Lloyd, A.C. Schwann Cells: Development and Role in Nerve Repair. Cold Spring Harb. Perspect. Biol. 2015, 7, a020487.
  2. Fisher, J.L.; Pettersson, D.; Palmisano, S.; Schwartzbaum, J.; Edwards, C.G.; Mathiesen, T.; Prochazka, M.; Bergenheim, T.; Florentzson, R.; Harder, H.; et al. Loud Noise Exposure and Acoustic Neuroma. Am. J. Epidemiol. 2014, 180, 58–67.
  3. Slattery, W.H. Neurofibromatosis type 2. Otolaryngol. Clin. N. Am. 2015, 48, 443–460.
  4. Evans, D.G.R.; Ramsden, R.T.; Shenton, A.; Gokhale, C.; Bowers, N.L.; Huson, S.M.; Pichert, G.; Wallace, A. Mosaicism in neurofibromatosis type 2: An update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J. Med. Genet. 2007, 44, 424–428.
  5. Yao, L.; Alahmari, M.; Temel, Y.; Hovinga, K. Therapy of Sporadic and NF2-Related Vestibular Schwannoma. Cancers 2020, 12, 835.
  6. Huang, C.W.; Tu, H.T.; Chuang, C.Y.; Chang, C.S.; Chou, H.H.; Lee, M.T.; Huang, C.F. Gamma Knife radiosurgery for large vestibular schwannomas greater than 3 cm in diameter. J. Neurosurg. 2018, 128, 1380–1387.
  7. Nakanishi, M.; Rosenberg, D.W. Multifaceted roles of PGE2 in inflammation and cancer. Semin. Immunopathol. 2013, 35, 123–137.
  8. Finetti, F.; Travelli, C.; Ercoli, J.; Colombo, G.; Buoso, E.; Trabalzini, L. Prostaglandin E2 and Cancer: Insight into Tumor Progression and Immunity. Biology 2020, 9, 434.
  9. Hong, B.; Krusche, C.A.; Schwabe, K.; Friedrich, S.; Klein, R.; Krauss, J.K.; Nakamura, M. Cyclooxygenase-2 Supports Tumor Proliferation in Vestibular Schwannomas. Neurosurgery 2011, 68, 1112–1117.
  10. Kandathil, C.K.; Dilwali, S.; Wu, C.-C.; Ibrahimov, M.; McKenna, M.J.; Lee, H.; Stankovic, K.M. Aspirin Intake Correlates with Halted Growth of Sporadic Vestibular Schwannoma In Vivo. Otol. Neurotol. 2014, 35, 353–357.
  11. Mackeith, S.; Wasson, J.; Baker, C.; Guilfoyle, M.; John, D.; Donnelly, N.; Mannion, R.; Jefferies, S.; Axon, P.; Tysome, J.R. Aspirin does not prevent growth of vestibular schwannomas: A case-control study. Laryngoscope 2018, 128, 2139–2144.
  12. Whitesell, L.; Lindquist, S.L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 2005, 5, 761–772.
  13. Chen, Z.; Li, S.; Mo, J.; Hawley, E.; Wang, Y.; He, Y.; Brosseau, J.-P.; Shipman, T.; Clapp, D.W.; Carroll, T.J.; et al. Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling. JCI Insight 2020, 5, e141514.
  14. Tanaka, K.; Eskin, A.; Chareyre, F.; Jessen, W.; Manent, J.; Kawakita, M.; Chen, R.; White, C.; Vitte, J.; Jaffer, Z.M.; et al. Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2. Clin. Cancer Res. 2013, 19, 3856–3870.
  15. Sagers, J.E.; Brown, A.S.; Vasilijic, S.; Lewis, R.M.; Sahin, M.I.; Landegger, L.D.; Perlis, R.H.; Kohane, I.S.; Welling, D.B.; Patel, C.J.; et al. Computational repositioning and preclinical validation of mifepristone for human vestibular schwannoma. Sci. Rep. 2018, 8, 5437.
  16. Nakanishi, H.; Kawashima, Y.; Kurima, K.; Chae, J.J.; Ross, A.M.; Pinto-Patarroyo, G.; Patel, S.K.; Muskett, J.A.; Ratay, J.S.; Chattaraj, P.; et al. NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy. Proc. Natl. Acad. Sci. USA 2017, 114, E7766–E7775.
  17. Hannan, C.J.; Lewis, D.; O’Leary, C.; Donofrio, C.A.; Evans, D.G.; Roncaroli, F.; Brough, D.; King, A.T.; Coope, D.; Pathmanaban, O.N. The inflammatory microenvironment in vestibular schwannoma. Neuro-Oncol. Adv. 2020, 2, vdaa023.
  18. Ren, Y.; Landegger, L.D.; Stankovic, K.M. Gene Therapy for Human Sensorineural Hearing Loss. Front. Cell. Neurosci. 2019, 13, 323.
  19. Prabhakar, S.; Taherian, M.; Gianni, D.; Conlon, T.J.; Fulci, G.; Brockmann, J.; Stemmer-Rachamimov, A.; Sena-Esteves, M.; Breakefield, X.O.; Brenner, G.J. Regression of Schwannomas Induced by Adeno-Associated Virus-Mediated Delivery of Caspase-1. Hum. Gene Ther. 2013, 24, 152–162.
  20. Ahmed, S.G.; Abdelnabi, A.; Maguire, C.A.; Doha, M.; Sagers, J.E.; Lewis, R.M.; Muzikansky, A.; Giovannini, M.; Stemmer-Rachamimov, A.; Stankovic, K.M.; et al. Gene therapy with apoptosis-associated speck-like protein, a newly described schwannoma tumor suppressor, inhibits schwannoma growth in vivo. Neuro-Oncology 2019, 21, 854–866.
  21. Ignacio, K.H.D.; Espiritu, A.I.; Diestro, J.D.B.; Chan, K.I.; Dmytriw, A.A.; Omar, A.T., 2nd. Efficacy of aspirin for sporadic vestibular schwannoma: A meta-analysis. Neurol. Sci. 2021, 42, 5101–5106.
  22. Tamura, R. Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis. Tamura R. Int. J. Mol. Sci. 2021, 22, 5850.