Abstract

Neurofibromatosis Type 2 (NF2) is a disorder of the nervous system, characterized by the formation of bilateral vestibular schwannoma tumors as well as meningioma and ependymoma tumors. Vestibular schwannomas are Schwann cell tumors that develop from the vestibulocochlear nerve and lead to deafness. NF2 is caused by mutations in the NF2 gene, encoding tumor suppressor protein merlin. NF2 tumors cause many symptoms depending on their location. The only NF2 treatments are surgery and radiosurgery which can impair nerve function, so alternative treatments such as drug-based therapies targeting pathways important for tumor formation, survival, and growth are needed. Targeting complementary pathways can be an effective way to overcome drug resistance. The Phosphoinositide 3 kinase (PI3K) and P21 activated kinases (PAK) pathways help control cellular processes related to tumor formation and are found dysregulated in merlin-deficient cells. Previous screening studies demonstrated synergistic effects of pictilisib (picti), an inhibitor of the PI3K pathway, and PF3758309 (PF), an inhibitor of PAK4 activity, on cell survival in merlin-null cells. To test the efficacy of this drug combination, a combination drug study was run using the NF2 allograft mouse peripheral nerve tumor model. Initial analyses revealed that these treatments and a combination may inhibit tumor growth. The purpose of this study was determining how PI3K and/or PAK inhibition by pictilisib and PF3758309 impact target protein levels in sciatic nerve NF2 allograft tumors. My role was analyzing tumors taken from the NF2 mice for targets proteins relevant to tumor growth and survival by conducting immunohistochemistry and ImageJ quantification. A secondary purpose was identifying possible deleterious side effects of drug treatment on healthy nerves with a qualitative assessment of contralateral sciatic nerves. Assessments support continued x evaluation of each drug for clinical use and show that the combination treatment can reduce cell proliferation and increase cell death.

Thesis Completion

2022

Semester

Spring

Thesis Chair/Advisor

Fernandez-Valle, Cristina

Degree

Bachelor of Science (B.S.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Language

English

Access Status

Campus Access

Length of Campus-only Access

5 years

Release Date

5-15-2028

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