From bench to bedside : elucidating vestibular schwannoma pathobiology to devise effective pharmacotherapies

Abstract

Vestibular schwannomas (VSs), the most common tumors of the cerebellopontine angle, arise from Schwann cells of the vestibular nerve. VSs can lead to sensorineural hearing loss (SNHL), disequilibrium, facial nerve paralysis, and brainstem compression. Treatment options available today are associated with significant morbidity, leading to an unmet need for well-tolerated pharmacotherapies to curb VS growth and associated SNHL. To identify pharmacologic targets, this thesis investigated inflammatory pathways in VS. Proinflammatory transcription factor nuclear factor kappa B (NF-KB) and enzyme cyclooxygenase 2 (COX- 2) were aberrantly active in VS. NF-KB inhibition, achieved through siRNA, an experimental agent BAYl 1-7082 or a clinically relevant drug curcumin, was cytotoxic against primary VS cells and HEI-193 VS cell line. COX-2 inhibition, achieved through salicylates, was cytostatic against primary VS cells. Our in vitro findings are in line with our retrospective findings that VS patients taking aspirin demonstrate halted tumor growth. Anti-inflammatory drugs such as aspirin could be efficacious against VS. Additionally, as the etiology of SNHL due to VS is unknown, this thesis explored the potential of VS secreted factors to modulate SNHL. Applying human VS secretions to organotypic cochlear explant cultures, we demonstrate that VS secreted factors can lead to hair cell and neurite degeneration. Exogenous application of tumor necrosis factor alpha (TNF[alpha]), an ototoxic cytokine whose VS secreted levels correlate with degree of SNHL, led to neurite loss in cochlear explants and TNF[alpha] neutralization in VS secretions partially rescued cochlear degeneration due to VS secretions. Interestingly, otoprotective fibroblast growth factor 2 (FGF2) levels in VS secretions inversely correlate with degree of SNHL, suggesting that different ototoxic and otoprotective VS-secreted molecules modulate VS's effect on hearing. TNF[alpha] and FGF2 could serve as biomarkers or pharmacologic targets against VS associated SNHL. Exploring angiogenic pathways, cross-talk between vascular endothelial growth factor (VEGF-A) and hepatocyte growth factor (HGF) was found in Schwann cells, VS cells and in cochlear cells. VEGF-A neutralization in VS secretions could not rescue cochlear degeneration but VEGF-A or HGF receptor knockdown was cytostatic in VS cells. Overall, several pathobiological pathways were investigated to provide promising therapeutic targets against neoplastic VS growth and associated SNHL.