characterizing-tumor-induced-ataxia-vestibular-schwannoma-mouse

Characterizing Tumor-Induced Ataxia in a Vestibular Schwannoma Mouse Model

NF2-related schwannomatosis (NF2-SWN) is an autosomal dominant tumor predisposition syndrome caused by germline mutations in the NF2 tumor suppressor ...

Harvard Medical School

NF2-related Schwannomatosis (NF2-SWN) is a disease that needs new solutions. The hallmark of NF2-SWN, a dominantly inherited neoplasia syndrome, is bilateral vestibular schwannomas (VSs), which progressively enlarge, leading to sensorineural hearing loss, tinnitus, facial weakness, and pain that translates to social impairment and clinical depression. Standard treatments for growing VSs include surgery and radiation therapy (RT); however, both carry the risk of further nerve damage that can result in deafness and facial palsy. The resultant suffering and debility, in combination with the paucity of therapeutic options, make the effective treatment of NF2-SWN a major unmet medical need. A better understanding of these mechanisms is essential to developing novel therapeutic targets to control tumor growth and improve patients' quality of life. Previously, we developed the first orthotopic cerebellopontine angle mouse model of VSs, which faithfully mimics tumor-induced hearing loss. In this model, we observed that mice exhibit symptoms of ataxia and vestibular dysfunction. Therefore, we further developed a panel of five tests suitable for the mouse VS model and investigated how tumor growth and treatment affect gait, coordination, and motor function. Using this panel of ataxia tests, we demonstrated that both ataxia and motor function deteriorated concomitantly with tumor progression. We further demonstrated that (i) treatment with anti-VEGF resulted in tumor size reduction, mitigated ataxia, and improved rotarod performance; (ii) treatment with crizotinib stabilized tumor growth and led to improvements in both ataxia and rotarod performance; and (iii) treatment with losartan did not impact tumor growth nor ameliorate ataxia or motor function. Our studies demonstrated that these methods, paired with hearing tests, enable a comprehensive evaluation of tumor-induced neurological deficits and facilitate the assessment of the effectiveness of novel therapeutics to improve NF2 treatments.

Integrating Ataxia Evaluation into Tumor-Induced Hearing Loss Model to Comprehensively Study NF2-Related Schwannomatosis.

-related Schwannomatosis (-SWN) remains a disorder with few effective treatment options. Patients develop vestibular schwannomas (VSs) on both auditory nerves, which gradually impair hearing and often result in significant communication difficulties, social withdrawal, and higher rates of depression. Progress in understanding -SWN biology and translating discoveries into therapies has been slowed by the absence of robust animal models that faithfully reproduce both tumor behavior and the associated neurological deficits. In this review, we summarized the development of animal models that not only reproduce tumor growth in the peripheral nerve microenvironment but also reproduce tumor-induced neurological symptoms, such as hearing loss and ataxia. We further highlight the currently available organotypic models for -SWN. Together, these systems provide an essential foundation for advancing mechanistic studies and accelerating the development of effective therapies for this devastating disorder.

Advancements in Preclinical Models for -Related Schwannomatosis Research.

NF2-related schwannomatosis (NF2-SWN) is a debilitating condition, characterized by bilateral vestibular schwannomas (VSs) that progressively cause irreversible sensorineural hearing loss. Current management relies on surgery or radiotherapy, while bevacizumab (αVEGF) is used off-label, with variable and often transient efficacy. Effective therapies that durably suppress tumor growth and preserve hearing are urgently needed. Although immune checkpoint inhibitors have transformed cancer treatment, their efficacy in non-malignant tumors such as VS remains unclear. Here, we evaluate combined anti-PD1 (αPD1) and αVEGF therapy in two syngeneic, immune-competent VS models. Combination treatment significantly outperforms either monotherapy, inhibiting tumor growth and preventing hearing loss. Mechanistically, αVEGF enhances αPD1 efficacy by normalizing tumor vasculature, improving drug delivery and immune cell infiltration, and promoting cytotoxicity of T and NK cells via NKG2D upregulation. Combined treatment effectively controls tumor growth that progresses despite anti-VEGF therapy. These findings support αPD1 and αVEGF combination therapy as a promising strategy for NF2-SWN.

NKG2D upregulation sensitizes tumors to combined anti-PD1 and anti-VEGF therapy and prevents hearing loss.

 -related schwannomatosis (-SWN) is a progressive neurological disorder with a hallmark of bilateral vestibular schwannomas (VSs), leading to irreversible hearing loss and reduced quality of life. To date, the FDA has not approved any pharmacological therapies for treating VS or hearing loss. While radiotherapy (RT) is the standard treatment for growing VSs, it often exacerbates hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their efficacy in non-malignant tumors like VS remains largely unexamined.  We used immune-competent VS mouse models to assess the efficacy of combined anti-PD1 (αPD1) and RT treatment, tumor growth, and hearing preservation.  We found three significant therapeutic benefits: i) RT induces immunogenic cell death and activates the STING pathway, enhancing αPD1 efficacy and generating long-term immune memory, ii) The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) RT to peripheral nerve tumor induces a systemic abscopal effect, which enhances αPD-1 efficacy to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury.  Our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and -SWN.

A cochlea-sparing strategy for non-invasive control of intracranial schwannomas via peripheral irradiation and anti-PD-1 therapy enhanced by STING activation.

Article	Year
Integrating Ataxia Evaluation into Tumor-Induced Hearing Loss Model to Comprehensively Study NF2-Related Schwannomatosis. Cancers\| PubMed ID: 38893082	2024
Advancements in Preclinical Models for -Related Schwannomatosis Research. Cancers\| PubMed ID: 41595145	2026
NKG2D upregulation sensitizes tumors to combined anti-PD1 and anti-VEGF therapy and prevents hearing loss. Nature communications\| PubMed ID: 41673019	2026
A cochlea-sparing strategy for non-invasive control of intracranial schwannomas via peripheral irradiation and anti-PD-1 therapy enhanced by STING activation. Theranostics\| PubMed ID: 41695475	2026

Simeng Lu

Biography

JoVE Journal Publications

Other Publications