Keywords

neurofibromatosis, schwannomatosis, NF2, schwannoma, MPNST, functional precision medicine

Subject Categories

Cancer Biology | Cell Biology | Pharmacology

Abstract

Schwann cells are the glial cell of the peripheral nervous system. They are dependent on receptor tyrosine kinase-mediated RAS signaling, cell matrix adhesion, and cell-cell contact to proliferate during nerve development and repair. These pathways become deregulated with loss of function of the merlin tumor suppressor encoded by NF2, leading to benign tumors called schwannomas. Patients with NF2-related schwannomatosis (NF2-SWN) develop bilateral vestibular schwannomas that cause hearing loss, tinnitus, and death from brainstem compression if untreated. Severe NF2-SWN causes multiple spinal and peripheral schwannomas and neuropathic pain. Schwannomas require careful monitoring, trial and error use of repurposed anti-cancer drugs, and radiotherapy to delay multiple debulking surgeries over a patient’s lifetime. There are no FDA approved NF2-SWN targeted therapeutics. The benign nature of patient schwannoma cells makes sufficient expansion for preclinical drug studies challenging. To determine if patient schwannoma cells are amenable to individualized study, high-content functional drug sensitivity assays were developed. Primary cells isolated from two unique schwannomas in a severe NF2-SWN patient were more sensitive to the cytostatic combination of FAK inhibitors, dasatinib and brigatinib, than the patient’s current treatment regimen for comorbid growing schwannomas. Primary schwannoma cells also responded to the dual HDAC/PI3K inhibitor fimepinostat with apoptotic cell death. Mechanistic studies in human schwannoma model cells suggest that fimepinostat inhibits HDAC2, modulates TNFR1/TRAIL R2 levels, and downregulates inhibitors of apoptosis and secretion of monocyte-recruitment cytokines (IL-8, MCP-1). Cell death was also observed in patient-derived malignant peripheral nerve sheath tumor cell lines treated with fimepinostat and the MEK inhibitor trametinib. These aggressive Schwann cell tumors arise in the related condition neurofibromatosis and are treated with resection and triple chemotherapy with low response rates. These findings demonstrate that high-content ex vivo cellular assays can identify promising alternatives to current therapeutic regimens for patients with numerous and aggressive Schwann cell tumors.

Completion Date

2026

Semester

Summer

Committee Chair

Fernandez-Valle, Cristina

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

PDF

Document Type

Dissertation

Language

English

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