Project Details
Description
Abstract
Hearing loss caused by noise, aging and chemotherapy affects seven hundred million people worldwide, but
there are no FDA-approved drugs to prevent it. This research will test the potential to repurpose a small
molecule BRAF inhibitor, dabrafenib (TAFINLAR), an FDA-approved drug for several cancers, for new use in
preventing cisplatin-induced hearing loss. Dabrafenib was a top hit in our unbiased high-throughput screens of
4,385 bioactive compounds and 187 specific kinase inhibitors for cisplatin-induced cell-death protection in an
inner ear cell line. We found that dabrafenib fully protected the outer hair cells against cisplatin toxicity in
mouse cochlear explants with IC50 of 30 nM and an excellent therapeutic index (LD50/IC50) of >2000.
Mechanistically, we identified dabrafenib and three additional BRAF inhibitors, two MEK1/2 inhibitors, and an
ERK1/2 inhibitor immediately downstream of BRAF in the cellular pathway, supporting the role of BRAF in
cisplatin-induced hair cell death. Cisplatin treatment of the inner ear cell line caused upregulation of phospho-
BRAF, phospho-MEK1/2 and phospho-ERK1/2 that was inhibited by co-treatment with dabrafenib. Moreover,
cisplatin treatment of cochlear explants or noise exposure in vivo caused up-regulation of phospho-ERK1/2
short time after damage in supporting cells (inner phalangeal and Deiters’ cells) that was mitigated by
dabrafenib treatment. Furthermore, at 100 nM dabrafenib protected zebrafish lateral line neuromasts from
cisplatin-induced death in vivo and, importantly, significant protection was achieved with oral delivery of
dabrafenib for three consecutive days in mouse models against cisplatin-induced hearing loss. The daily dose
of dabrafenib administered to the mice was in the range approved for long-term human treatment. In this
proposal, we will test the protection provided by dabrafenib for cisplatin-induced hearing loss in a multiple low
dose cisplatin regimen that mimics closely the cisplatin treatment of cancer patients in the clinic. Functional
auditory performance and inner ear morphology will be assessed. Two doses of dabrafenib will be tested to
evaluate the therapeutic window of the drug in vivo. We will also determine dabrafenib’s interference with
cisplatin tumor killing efficacy in tumor cell lines and mouse tumor models in which cisplatin is the standard
treatment, neuroblastoma and lung cancer. We will confirm BRAF kinase is the molecular target of dabrafenib
in cisplatin-induced hearing loss by generating a supporting cell specific conditional knockout mouse in which
BRAF is specifically deleted in the supporting cells of the inner ear starting at postnatal day 28 and testing its
resistance to cisplatin. Supporting cells’ ERK phosphorylation can serve as an in vivo biomarker for cisplatin
damage and evaluating treatment with BRAF inhibitors and can be utilized to determine dabrafenib’s PK/PD
properties. Our study will reveal a new cellular pathway and molecular target BRAF kinase for otoprotection
and will provide the crucial data needed for advancing dabrafenib to clinical trials in humans for prevention of
cisplatin-induced hearing loss.
Status | Active |
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Effective start/end date | 1/1/21 → 12/31/23 |
Funding
- National Institute on Deafness and Other Communication Disorders: $402,857.00
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