Repurposing an FDA Approved Drug, B-Raf Inhibitor Dabrafenib, for Protection from Cisplatin- and Noise-Induced Hearing Loss

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Hearing loss caused by noise, aging, antibiotics and chemotherapy affects seven hundred million people worldwide, yet there are no FDA-approved drugs to prevent it. This proposal is to optimize an FDA-approved, orally bioavailable small molecule B-Raf kinase inhibitor, dabrafenib (TAFINLAR), to prevent or treat cisplatin- and noise-induced hearing loss (CIHL and NIHL, respectively). Taking advantage of the significant overlap in the molecular pathways activated in CIHL and NIHL, unbiased high-throughput screens of 4,385 bioactive compounds (Teitz et al., 2018) and 187 highly-specific kinase inhibitors (unpublished) that reduced cisplatin- induced cell-death in an inner ear cell line (HEI-OC1) revealed dabrafenib as the best hit. Dabrafenib is a potent selective small molecule inhibitor of B-Raf kinase for treating advanced melanoma and non-small cell lung carcinoma. This drug prevented cisplatin-induced hair cell death in vitro, with IC50 of 30 nM and therapeutic index >2000, and 70-3,280 times better than four other benchmark otoprotectants (sodium thiosulfate, ebselen, D- methionine and dexamethasone; preliminary data and Teitz et al., JEM 2018). Three additional B-Raf inhibitors and two MEK1/2 inhibitors (directly downstream from B-Raf kinase) also prevented cisplatin-induced hair cell death in cochlear explants. Furthermore, oral dabrafenib provided significant protection in mouse models of CIHL and NIHL. The daily dose of dabrafenib administered to mice was in the range approved for chronic human treatment (6-12 months). Therefore, we hypothesize that dabrafenib can be rapidly repurposed for oral delivery to humans to prevent CIHL and NIHL. Because preclinical and clinical toxicity profiles of dabrafenib are already approved by FDA, the proposed work focuses on the necessary nonclinical experiments for determining dabrafenib’s efficacy for expedited translation into clinical use to benefit patients at high risk of CIHL and NIHL. Testing the different schedules to prevent CIHL and NIHL as described in this proposal will allow to identify the most important regimens for human clinical trials. The study will also reveal a new cellular pathway and molecular target B-Raf kinase for otoprotection. The completion of the studies will lead to one of the first FDA- approved drugs repurposed for the prevention and treatment of hearing loss.