{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T12:29:08Z","timestamp":1770640148833,"version":"3.49.0"},"reference-count":44,"publisher":"Journal of Neurosurgery Publishing Group (JNSPG)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,1]]},"abstract":"<jats:sec>\n<jats:title>OBJECTIVE<\/jats:title>\n<jats:p>Vestibular schwannomas (VSs) are benign nerve sheath tumors that result from mutation in the tumor suppressor gene <jats:italic>NF2<\/jats:italic>, with functional loss of the protein merlin. The authors have previously shown that c-Jun N-terminal kinase (JNK) is constitutively active in human VS cells and plays a central role in their survival by suppressing accumulation of mitochondrial superoxides, implicating JNK inhibitors as a potential systemic treatment for VS. Thus, the authors hypothesized that the adenosine 5\u02b9-triphosphate\u2013competitive JNK inhibitor AS602801 would demonstrate antitumor activity in multiple VS models.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>METHODS<\/jats:title>\n<jats:p>Treatment with AS602801 was tested in primary human VS cultures, human VS xenografts, and a genetic mouse model of schwannoma (<jats:italic>Postn-Cre;Nf2<jats:sup>flox\/flox<\/jats:sup><\/jats:italic>). Primary human VS cell cultures were established from freshly obtained surgical tumor specimens; treatment group media was enriched with AS602801. VS xenograft tumors were established in male athymic nude mice from freshly collected human tumor. Four weeks postimplantation, a pretreatment MRI scan was obtained, followed by 65 days of AS602801 (n = 18) or vehicle control (n = 19) treatment. Posttreatment MRI scans were used to measure final tumor volume. Tumors were then harvested. Finally, <jats:italic>Postn-Cre;Nf2<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> mice were treated with AS602801 (n = 10) or a vehicle (n = 13) for 65 days. Posttreatment auditory brainstem responses were obtained. Dorsal root ganglia from <jats:italic>Postn-Cre;Nf2<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> mice were then harvested. In all models, schwannoma identity was confirmed with anti-S100 staining, cell proliferation was measured with the EdU assay, and cell death was measured with terminal deoxynucleotidyl transferase\u2013mediated dUTP nick-end labeling staining. All protocols were approved by the local institutional review board and Institutional Animal Care and Use Committees.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>RESULTS<\/jats:title>\n<jats:p>Treatment with AS602801 decreased cell proliferation and increased apoptosis in primary human VS cultures. The systemic administration of AS602801 in mice with human VS xenografts reduced tumor volume and cell proliferation. Last, the AS602801-treated <jats:italic>Postn-Cre;Nf2<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> mice demonstrated decreased cell proliferation in glial cells in the dorsal root ganglia. However, AS602801 did not significantly delay hearing loss in <jats:italic>Postn-Cre;Nf2<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> mice up to 3 months posttreatment.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>CONCLUSIONS<\/jats:title>\n<jats:p>The data suggest that JNK inhibition with AS602801 suppresses growth of sporadic and neurofibromatosis type 2\u2013associated VSs. As such, AS602801 is a potential systemic therapy for VS and warrants further investigation.<\/jats:p>\n<\/jats:sec>","DOI":"10.3171\/2022.7.jns22934","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T17:52:03Z","timestamp":1662745923000},"page":"962-971","source":"Crossref","is-referenced-by-count":3,"title":["Reduction of sporadic and neurofibromatosis type 2\u2013associated vestibular schwannoma growth in vitro and in vivo after treatment with the c-Jun N-terminal kinase inhibitor AS602801"],"prefix":"10.3171","volume":"138","author":[{"given":"Mark C.","family":"Dougherty","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, University of Iowa, Iowa City;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiji B.","family":"Shibata","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of Iowa, Iowa City, Iowa; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Jason","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of Iowa, Iowa City, Iowa; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franklin J.","family":"Canady","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of Iowa, Iowa City, Iowa; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles W.","family":"Yates","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Indiana University School of Medicine, Indianapolis, Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marlan R.","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of Iowa, Iowa City, Iowa; and"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1754","reference":[{"issue":"5","key":"b1","series-title":"J Neurosurg","first-page":"906","article-title":"The molecular biology and novel treatments of vestibular schwannomas","volume":"115","author":"Fong B","year":"2011","unstructured":"Fong B, Barkhoudarian G, Pezeshkian P, Parsa AT, Gopen Q, Yang I. 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