EXTH-13. REDUCTION OF TUMOR BURDEN AND HEARING LOSS WITH A MULTIPLE RECEPTOR TYROSINE KINASE INHIBITOR BRIGATINIB IN A GENETICALLY ENGINEERED MOUSE MODEL OF NEUROFIBROMATOSIS TYPE 2
Аннотация:Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic disorder caused by germline mutations in the tumor suppressor gene NF2, which encodes the protein Merlin. Patients with NF2 may develop bilateral vestibular schwannomas, which cause hearing impairment, and schwannomas in other regions of the nervous system. Due to the nature and location of the tumors, there is high morbidity and mortality associated with NF2, and no known effective chemotherapeutic intervention. A high-throughput in vitro cell viability screen revealed an Anaplastic Lymphoma Kinase (ALK) inhibitor as a top contender for selective inhibition of Nf2-deficient murine Schwann cells. Brigatinib (Alunbrig®) is a small molecule multiple receptor tyrosine kinase inhibitor that is FDA-approved for ALK-positive metastatic non-small cell lung cancer. Therefore, we hypothesized that brigatinib would prevent tumorigenesis in our genetically engineered mouse model of NF2 (Nf2f/f; Postn-Cre+). 50mg/kg Brigatinib was administered to Nf2f/f; Postn-Cre+ mice by oral gavage daily for 12 weeks. Pharmacokinetic analyses paired with immunohistochemistry showed brigatinib is orally bioavailable, and treatment resulted in a therapeutically relevant concentration of brigatinib in the plasma (cmax = 4.8µM; tmax = 4hrs), which was sufficient to induce a biological response in the dorsal root ganglia (DRG) schwannomas. The volume of DRG in brigatinib-treated mice was 55% less than vehicle-treated mice. Additionally, brigatinib-treated mice did not have significant progression of hearing loss at the end of treatment, whereas vehicle-treated mice had a statistically significant 7.4dB increase in ABR threshold. Finally, histopathological assessment of DRG shows that brigatinib treatment prevented the progressive morphological disruption observed in the vehicle-treated mice. These data provide evidence that brigatinib targets may play a significant role in Merlin-deficient schwannomagenesis, and implicate brigatinib as a promising therapeutic intervention of NF2.
