Novel Mechanistic Insights and Therapeutic Strategies for Vestibular Schwannoma and Neurofibromatosis Type 2
Sagers, Jessica Elysse
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CitationSagers, Jessica Elysse. 2019. Novel Mechanistic Insights and Therapeutic Strategies for Vestibular Schwannoma and Neurofibromatosis Type 2. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractVestibular schwannoma (VS) is a debilitating intracranial tumor and an important cause of genetic human sensorineural hearing loss (SNHL). VSs arise from neoplastic Schwann cells of the vestibular nerves and typically cause progressive SNHL and tinnitus. As these tumors grow, they can compress the brainstem and cause death. Bilateral VSs develop as the hallmark of neurofibromatosis type 2 (NF2), an autosomal dominant monogenic disorder typically manifesting in adolescence. All NF2-associated VSs and the vast majority of sporadically arising VSs are accompanied by mutation of the NF2 gene, which encodes the tumor suppressor protein merlin. There are no FDA-approved drug therapies for NF2 or VS, and existing cellular models of these diseases are severely limited. My dissertation proposes and evaluates novel therapeutic strategies to treat and model VS and NF2. Specifically, my work comprises five first-author manuscripts detailing the optimization of processing and culture of primary human VS samples from the operating room; the relationship between cochlear histopathology and clinical observations in VS and primary neural degeneration; the in silico screening of FDA-approved drugs for repositioning in NF2 and VS; the cellular-level preclinical validation of a novel hit compound, the progesterone receptor antagonist mifepristone, which arrests VS cell growth in vitro and has prompted the design of a Phase II clinical trial in VS patients; the validation of a novel combination small molecule therapy targeting mTOR- and EPH receptor-mediated signaling in primary human VS cells; and the emerging role of the NLRP3 inflammasome in VS. My dissertation highlights the need for ongoing work towards the generation of viable, diverse human cellular models for VS and NF2, which can be used to facilitate preclinical drug discovery and expedite translation to the clinic.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42029598
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