Drug Therapy in Vestibular Schwannoma

Vestibular schwannomas (VSs, also known as acoustic neuromas) are benign intracranial tumors commonly managed with observation, surgery, and radiotherapy. There is currently no approved pharmacotherapy for VS patients, which is why we conducted a detailed search of relevant literature from PubMed and Web of Science to explore recent advances and experiences in drug therapy. VSs feature a long course of disease that requires treatment to have minimal long-term side effects. Conventional chemotherapeutic agents are characterized by neurotoxicity or ototoxicity, poor effect on slow-growing tumors, and may induce new mutations in patients who have lost tumor suppressor function, and therefore are unsuitable for treating VSs. Along with the well-investigated molecular pathophysiology of VS and the increasingly accessible technology such as drug repositioning platform, many molecular targeted inhibitors have been identified and shown certain therapeutic effects in preclinical experiments or clinical trials.

As the most common tumors of the cerebellopontine angle and the fourth most common intracranial neoplasms, vestibular schwannomas (VSs) are histopathologically benign neoplasms that typically originate from Schwann cells lining cranial nerve VIII (vestibular nerve). Neurosurgeons have determined that hearing loss, deafness, and tinnitus are common clinical manifestations in the early stages of VSs, and that progressive VSs are likely to impact lower cranial nerves and the brainstem, leading to facial paresthesia, ataxia and vertigo. With the progress of diagnosis and treatment technology, the main purpose of VS management has changed from saving patients’ lives to preserving complete neurological function and improving their quality of life.

VSs can occur unilaterally, as sporadic lesions, or bilaterally, as a part of autosomal dominantly inherited disorder neurofibromatosis type 2 (NF2). About 60% of unilateral VSs and 90% of bilateral cases demonstrate the mutation of the NF2 gene and the dysfunction of its transcription product, merlin (Moesin-ezrin-radixin-like protein). Strategies for managing patients with sporadic VS are observation, surgery, and radiotherapy. Over the 3.6-year follow-up, the average growth rate for sporadic tumors was 1.1 mm/year, suggesting that “wait and rescan” with serial MRIs is a safe choice for small and stable tumors (<2cm), as well as for elderly patients, whose treatment is associated with a higher mortality rate. However, this tactic is associated with risk of tumor growth and poor hearing outcomes. Surgical treatment can cause significant trauma to patients, thus it is only preferable in patients with symptoms of brainstem compression or with small but fast-growth tumors. Radiotherapy is suitable for small growing tumors and small tumors with an irregular outline. Additionally, pseudo progression, damage to cochlear hair cells, delayed hearing loss, and surgically challenging post-stereotactic radiosurgery should be taken into consideration. NF2-VSs are more lobulated, grow more quickly, present at a younger age, tend to be larger, envelop adjacent cochlear and facial nerves, and may coexist with schwannomas of the facial and cochlear nerves, making the cleavage plane between the facial nerve and the tumor difficult to determine, thus higher risk of nerve damage secondary to surgery. It is widely accepted that radiotherapy is less effective in treating NF2-VSs than treating sporadic VSs.

The growing understanding of the mechanisms by which merlin dysregulation induces disease, as well as of signal pathways related to VS growth, has raised hopes for the application of targeted therapies. Merlin plays a significant role in regulating the process mediated by the actin cytoskeleton, adhesion junction formation, and cell proliferation. Recent studies have suggested that merlin can regulate multiple pathways implicated in tumorigenesis including retrovirus-associated DNA sequences (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen extracellular signal-regulated kinase (MEK)/extracellular-signal-regulated kinases (ERK), mammalian target of rapamycin complex 1 (mTORC1), Rac/p21-activated kinase (PAK)/C-Jun kinase, phosphoinositide 3-kinase (PI3K)/Akt and the intranuclear E3 ubiquitin ligase CRL4 (DCAF1). All of these proposed sites are potential therapeutic targets of VS.

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