An allograft mouse model for the study of hearing loss secondary to vestibular schwannoma growth

Bonne, N.-X.; Vitte, Jérémie; Chareyre, Fabrice; Karapetyan, G. R.; Khankaldyyan, Vazgen; Moats, Rex; Giovannini, Marco

doi:10.1007/s11060-016-2150-9

Cited by 11 publications

(17 citation statements)

References 41 publications

(50 reference statements)

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“…Second, using this model, evaluation of the neurological function is limited to rotarod assay, which only assesses motor coordination and does not reflect sensory function. Future preclinical efficacy studies using the orthotopic models [52][53][54] and NF2 genetically engineered mouse models [45][46][47][48][49][50] will complement the current study and facilitate translation to clinic. Though dasatinib has been associated with some toxicity in the clinic, we did not observe systemic toxicity (body weight loss) in mice treated with AZD2014, dasatinib, or combination therapy.…”

Section: Discussionmentioning

confidence: 99%

Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma

Sagers

Beauchamp

Zhang

et al. 2020

Sci Rep

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Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by bilateral vestibular schwannomas (VS) that arise from neoplastic Schwann cells (SCs). NF2-associated VSs are often accompanied by meningioma (MN), and the majority of NF2 patients show loss of the NF2 tumor suppressor. mTORC1 and mTORC2-specific serum/glucocorticoid-regulated kinase 1 (SGK1) are constitutively activated in Mn with loss of NF2. In a recent high-throughput kinome screen in NF2-null human arachnoidal and meningioma cells, we showed activation of EPH RTKs, c-KIT, and SFK members independent of mTORC1/2 activation. Subsequently, we demonstrated in vitro and in vivo efficacy of combination therapy with the dual mTORC1/2 inhibitor AZD2014 and the multi-kinase inhibitor dasatinib. For these reasons, we investigated activated mTORC1/2 and EPH receptor-mediated signaling in sporadic and NF2-associated VS. Using primary human VS cells and a mouse allograft model of schwannoma, we evaluated the dual mTORC1/2 inhibitor AZD2014 and the tyrosine kinase inhibitor dasatinib as monotherapies and in combination. Escalating dose-response experiments on primary VS cells grown from 15 human tumors show that combination therapy with AZD2014 and dasatinib is more effective at reducing metabolic activity than either drug alone and exhibits a therapeutic effect at a physiologically reasonable concentration (~0.1 µM). In vivo, while AZD2014 and dasatinib each inhibit tumor growth alone, the effect of combination therapy exceeds that of either drug. Co-targeting the mTOR and EPH receptor pathways with these or similar compounds may constitute a novel therapeutic strategy for VS, a condition for which there is no FDA-approved pharmacotherapy. Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle and the fourth most common intracranial tumor in humans. VSs are formed from neoplastic Schwann cells of the vestibular nerve and can arise sporadically or as part of a debilitating tumor syndrome known as neurofibromatosis type 2 (NF2) that can include multiple schwannomas, meningiomas, and ependymomas 1. The majority of VS patients generally report sensorineural hearing loss and tinnitus, with others experiencing dizziness, loss of balance, or facial

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Section: Discussionmentioning

confidence: 99%

Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma

Sagers

Beauchamp

Zhang

et al. 2020

Sci Rep

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“…VSs are intracranial, extraaxial tumors that arise from the Schwann cell sheath of the eighth cranial nerve. A recent study reported an allograft model of implanting schwannoma cells to the auditory-vestibular nerve complex, and tumor growth impaired hearing (41). However, because the tumor cells were injected through the internal auditory canal, the surgery and injection caused hearing loss that took up to 14 d to recover.…”

Section: Discussionmentioning

confidence: 99%

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models

Zhao

Liu

Zhang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth causes progressive hearing loss, and the standard treatment, including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allow hearing testing. Here, we developed a cerebellopontine angle (CPA) schwannoma model that faithfully recapitulates the tumor-induced hearing loss. Using this model, we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor hepatocyte growth factor (HGF) levels. This cMET gene knockdown study independently confirmed the role of the cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared with normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in patients with NF2.

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“…The mouse allograft model consists of infusion of a Schwann cell line (SC4-9 luc ), derived from Nf2 -knockout mice and transformed to express luciferase, into the CPA of nude mice. 20 However, the stereotactic and microsurgical techniques utilized in this animal model are technically challenging and require years to master. Sham-injected mice also developed immediate shifts on ABR testing after implantation, that although improved partially with time, further depicts the challenges in reproducing this model by novice investigators.…”

Section: Discussionmentioning

confidence: 99%

“…Bonne et al (2016) introduced an allograft model for VS created by orthotopic grafting of the SC4 Schwann cell line onto the cochleovestibular nerve by infusing cells embedded in Matrigel® into the cerebellopontine angle (CPA) through microsurgical or stereotactic approaches. 20 This allograft model develops tumors as early as day 11 that can be detected with bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). Mice also develop HL on auditory brainstem response (ABR) tests.…”

Section: Introductionmentioning

confidence: 99%

A Xenograft Model of Vestibular Schwannoma and Hearing Loss

Dinh

Bracho

Mei

et al. 2018

Otology &Amp; Neurotology

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An allograft mouse model for the study of hearing loss secondary to vestibular schwannoma growth

Cited by 11 publications

References 41 publications

Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma

Combination therapy with mTOR kinase inhibitor and dasatinib as a novel therapeutic strategy for vestibular schwannoma

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models

A Xenograft Model of Vestibular Schwannoma and Hearing Loss

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