The molecular biology and novel treatments of vestibular schwannomas

Abstract

Vestibular schwannomas are histopathologically benign tumors arising from the Schwann cell sheath surrounding the vestibular branch of cranial nerve VIII and are related to the NF2 gene and its product merlin. Merlin acts as a tumor suppressor and as a mediator of contact inhibition. Thus, deficiencies in both NF2 genes lead to vestibular schwannoma development. Recently, there have been major advances in our knowledge of the molecular biology of vestibular schwannomas as well as the development of novel therapies for its treatment. In this article the authors comprehensively review the recent advances in the molecular biology and characterization of vestibular schwannomas as well as the development of modern treatments for vestibular schwannoma. For instance, merlin is involved with a number of receptors including the CD44 receptor, EGFR, and signaling pathways, such as the Ras/raf pathway and the canonical Wnt pathway. Recently, merlin was also shown to interact in the nucleus with E3 ubiquitin ligase CRL4(DCAF1). A greater understanding of the molecular mechanisms behind vestibular schwannoma tumorigenesis has begun to yield novel therapies. Some authors have shown that Avastin induces regression of progressive schwannomas by over 40% and improves hearing. An inhibitor of VEGF synthesis, PTC299, is currently in Phase II trials as a potential agent to treat vestibular schwannoma. Furthermore, in vitro studies have shown that trastuzumab (an ERBB2 inhibitor) reduces vestibular schwannoma cell proliferation. With further research it may be possible to significantly reduce morbidity and mortality rates by decreasing tumor burden, tumor volume, hearing loss, and cranial nerve deficits seen in vestibular schwannomas.

Hearing disorders in brainstem lesions

“…Asthagiri et al (2009) suggest that the optimum treatment should be multidisciplinary. Recently novel therapies have been proposed aimed at inducing inhibition of angiogenesis and regulation of the epidermal growth factor receptor family of receptors (Fong et al, 2011;Blakeley, 2012;Plotkin et al, 2012;Yener et al, 2012). The effectiveness of this chemotherapy is still under evaluation.…”

Vestibuler Schwannoma Bir Otopsi Olgusu ve Kaynakların Gözden Geçirilmesi

“…Vestibulocochlear (8. kranial) sinirin vestibüler bölümünde, schwann kılıfı hücrelerinden kaynaklanan ve benign intra kranial tümör olan Vestibuler Schwannoma, t ü m i n t r a k r a n i a l n e o p l a z i l e r i n % 1 -1 0 ' u n u oluşturmaktadır (1,2,3,4). Tüm Schwannomaların %60'ı, tüm intrakranial Schwannomaların ise %90'ı Vestibuler Schwannoma olarak tanımlanmaktadır (5).…”

Editorial: Therapeutic targeting based on gene-expression profiling in vestibular schwannomas

“…Gelareh zaDeh, M.D., Ph.D., 7 saMeer aGnihotri, Ph.D., 1 isabel GuGel, M.D., 2 Marc reMke, M.D., 1,3,4 antje borneMann, M.D., Ph.D., 5 GeorGios Pantazis, M.D., 6 stePhen c. We are grateful to Drs. Peruzzi and Lonser for their positive review of our work and for highlighting some of the key points arising from the results we obtained in our study.…”

“…4,5,13 Others have described the role of merlin (the protein produced by the NF2 gene) as a direct negative regulator of mTOR. 6 Because of the involvement of these pathways in cell cycle activation/apoptosis inhibition, they have been found frequently overexpressed in cancers and represent a therapeutic target for inhibition leading to growth arrest and apoptosis.…”