Research ArticleCancer

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

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Science Translational Medicine  14 Jul 2021:
Vol. 13, Issue 602, eabd4816
DOI: 10.1126/scitranslmed.abd4816

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Hearing preservation

The neoplastic syndrome neurofibromatosis type 2 (NF2) is characterized by the growth of vestibular schwannomas (VSs), benign tumors that develop along the acoustic nerve leading to hearing loss. Now, Wu et al. used the antihypertensive drug, losartan, to inhibit fibrogenic and inflammatory angiotensin signaling in a mouse model of NF2 and showed that the treatment prevented hearing loss and normalized the tumor microenvironment by targeting IL6/STAT3 signaling. In patient-derived material, IL6 was associated with cochlear cell loss, and analysis of clinical data revealed that patients with NF2 who were taking angiotensin receptor blockers were less likely to develop hearing loss, suggesting that losartan could be repurposed for treating patients with VSs.

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.

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