Abstract

Neurofibromatosis type 2 (NF2) is a debilitating disease characterized by the formation of bilateral vestibular schwannomas, which compress the vestibulocochlear nerve and cause deafness. Additional peripheral schwannomas, meningiomas and ependymomas may also form. NF2 is caused by mutations in the NF2 gene, resulting in the loss of function of the merlin tumor suppressor. Merlin functions in multiple signaling pathways and its absence in Schwann cells yields increased cell survival and proliferation, thereby causing schwannoma formation. First line treatment for NF2 is watchful waiting and surgical removal of tumors, potentially resulting in facial paralysis and deafness. To date, there are no pharmacological options for patients with NF2. Since the first clinical trials were completed in 2012, only 5 drugs have been investigated in NF2 patients. Few drugs have elicited a measurable radiographic tumor response and most only result in temporary hearing improvement in a small subset of patients. Development of novel therapeutic compounds is a slow, expensive process. However, re-purposing FDA-approved drugs for NF2 accelerates the transfer of efficacious drugs to the clinic. This dissertation used a systematic approach to identify drugs capable of reducing NF2-associated schwannoma growth. An initial screen revealed drugs that reduced viability of mouse and human merlin-deficient Schwann cells. Efficacious drugs were then advanced to an allograft mouse model of NF2 to identify those that reduced tumor growth in vivo. Drug efficacy was also examined in human primary schwannoma cells. We showed that Src, c-MET and MEK inhibitors reduced viability of merlin-deficient Schwann cells both in vitro and in vivo. We also identified a combination treatment of Src and c-MET inhibitors that induced apoptosis, suggesting the potential for preventing tumor recurrence after completion of drug treatment. The work presented here provides valuable pre-clinical evidence for the advancement of several approved drugs to clinical trials for NF2-associated schwannomas.

Notes

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Graduation Date

2017

Semester

Fall

Advisor

Fernandez-Valle, Cristina

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Degree Program

Biomedical Sciences

Format

application/pdf

Identifier

CFE0006877

URL

http://purl.fcla.edu/fcla/etd/CFE0006877

Language

English

Release Date

December 2022

Length of Campus-only Access

5 years

Access Status

Doctoral Dissertation (Open Access)

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