Targeting HMGB1 to improve hearing andenhance therapy for Vestibular Schwannomas

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Abstract Neurofibromatosis type 2 (NF2) is a devastating disease that needs effective treatments. The hallmark of NF2 is bilateral vestibular schwannomas (VSs), which progressively enlarge and lead to hearing loss and substantial negative impacts to quality of life. Identifying well-tolerated drugs to halt VS growth and ameliorate VS-associated hearing loss is a major unmet medical need. The greatest barrier to managing NF2-related auditory impairment is our incomplete understanding of how tumors cause hearing loss. We aim to investigate the mechanisms of VS tumor- induced hearing loss and develop strategies to control VS tumor growth while preventing hearing loss. Our preliminary studies showed that i) the level of neuroinflammation, including macrophage infiltration and NLRP3 inflammasome activation, negatively correlates with hearing function in patients with VS, and ii) patients’ VSs secrete inflammatory cytokines and cause cochlear damage. Therefore, we explored the drivers of neuroinflammation in VS. We identified that Highly Mobility Group Box1 (HMGB1), a potent inflammation initiator and amplifier, is abundantly secreted by VS tumor cells. Further, we found that HMGB1 blockade: iii) reduced macrophage chemokine CCL motif chemokine ligand 2 (CCL2) expression and tumor-associated macrophage (TAM) recruitment, iv) abolished NLRP3 inflammasome activation and IL-1b production, however, v) HMGB1 blockade activates epidermal growth factor (EGF) signaling, which may compensate for tumor growth. Based on these findings, we hypothesize that VS-derived HMGB1: i) recruits inflammatory macrophages by upregulating the CCL2 chemokine, ii) drives the macrophage inflammatory cascade by activating the NLRP3 inflammasome, contributing to cochlear damage and hearing loss; and iii) combined HMGB1 and EGF receptor (EGFR) blockade will concurrently suppress VS growth and prevent tumor-induced hearing loss. In Aim 1, we will use genetic silencing of HMGB1 and Nlrp3 to investigate the causal role of HMGB1 in regulating CCL2 expression to recruit macrophages and in activating NLRP3 inflammasome to trigger the macrophage inflammatory response. In Aim 2, using VS mouse models that faithfully reproduce VS tumor- induced hearing loss, we will characterize the effects of HMGB1 pharmacologic inhibition on hearing function and cochlear damage. In Aim 3, we will determine the most effective EGFR inhibitor to control tumor growth and characterize the pharmacokinetic/pharmacodynamic properties of HMGB1 and EGFR inhibitors in the tumor, mouse brain, and cochlea. Then, using the most effective HMGB1 and EGFR inhibitor identified, we will evaluate the treatment efficacy of combined HMGB1 and EGFR blockade on tumor growth and hearing in VS mouse models. Impact: This study will provide pivotal insight into i) the role and mechanisms of HMGB1 in driving neuroinflammation, ii) the treatment potential and the hearing response following HMGB1 blockade, and iii) the design of a future clinical trial for NF2-related VS using a novel combination strategy with HMGB1 and EGFR blockade to concurrently control tumor growth and prevent VS-induced hearing loss.