Losartan prevents tumor-induced hearing loss and augments radiation efficacy in NF2 schwannoma rodent models

Abstract

Hearing loss is one of the most common symptoms of neurofibromatosis type 2 (NF2) caused by vestibular schwannomas (VSs). Fibrosis in the VS tumor microenvironment (TME) is associated with hearing loss in patients with NF2. We hypothesized that reducing the fibrosis using losartan, an FDA-approved antihypertensive drug that blocks fibrotic and inflammatory signaling, could improve hearing. Using NF2 mouse models, we found that losartan treatment normalized the TME by (i) reducing neuroinflammatory IL-6/STAT3 signaling and preventing hearing loss, (ii) normalizing tumor vasculature and alleviating neuro-edema, and (iii) increasing oxygen delivery and enhancing efficacy of radiation therapy. In preparation to translate these exciting findings into the clinic, we used patient samples and data and demonstrated that IL-6/STAT3 signaling inversely associated with hearing function, that elevated production of tumor-derived IL-6 was associated with reduced viability of cochlear sensory cells and neurons in ex vivo organotypic cochlear cultures, and that patients receiving angiotensin receptor blockers have no progression in VS-induced hearing loss compared with patients on other or no antihypertensives based on a retrospective analysis of patients with VS and hypertension. Our study provides the rationale and critical data for a prospective clinical trial of losartan in patients with VS.

Sporadic Vestibular Schwannoma Size and Location Do not Correlate With the Severity of Hearing Loss at Initial Presentation

“…Parallel studies showcase the abundance of tumorsecreted factors, such as matrix metalloproteinase-14 (MMP-14), capable of causing SNHL through spiral ganglion neuron fiber and synapse damage (8). Additional molecular biomarkers identified throughout the inflammatory microenvironment of VS that may contribute toward tumor-induced hearing loss include tumor necrosis factor alpha (TNFa), IL-6, CXCR4, and nuclear factor kappa-B (NFkB) activation (50)(51)(52)(53).…”

Potential Molecular Biomarkers of Vestibular Schwannoma Growth: Progress and Prospects

“…Nevertheless, merlin-deficient Schwann cells may not accurately reproduce VS ( 162 ), and it takes more than 2 weeks for the construction of mouse model. Recently proposed zebrafish xenograft model with shorter period of model establishment ( 163 ), as well as the application of 3D in vitro cell culture system ( 164 ) and ex vivo organ cultures ( 165 ) that fully mirror the growth patterns of VS, promise to further elucidate the role of these biomolecules in the pathogenesis of VS. Second, clinical validation of these hypotheses should take tumor diameter and clinical course into consideration. Current studies demonstrate non-linear changes of protein expression as VS size increases ( 45 ), suggesting that tumor progression at different grades might be stimulated by different signaling pathways and can therefore be predicted by different biomarkers.…”

Continuously perfusable, customisable and matrix-free vasculature on a chip platform

“…Our VoC-OVAA will enable investigating a variety of key mechanisms in vascular biology which have physio pathologic implications. For example, cancer-associated signalling and extracellular matrix stiffening has been associated with impaired vascular maturation and reduced oxygenation of cancer tissue (Wu et al, 2021). Vascular abnormalities are also associated with impaired delivery of chemotherapies and immunotherapies with overall worse prognosis, and vascular normalisation therapy represents a very promising avenue to improve therapy outcome (Jain, 2005).…”