Thursday, November 21, 2024 11/21/2024

Repurposing an FDA approved Drug, B-Raf Kinase Inhibitor Dabrafenib for Protection from Cisplatin- and Noise- induced Hearing Loss

Award Number: R01DC018850
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $533,268 )
2024	2024	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	002	4	8/22/2024	NON-COMPETING CONTINUATION	-$402,856
2024	2024	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	001	4	5/3/2024	NON-COMPETING CONTINUATION	$40,286
2024	2024	THE SCINTILLON INSTITUTE	6868 NANCY RIDGE DR STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Research Related to Deafness and Communication Disorders	003	5	8/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$533,267
2024	2024	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	4	12/12/2023	NON-COMPETING CONTINUATION	$362,571
														Subtotal = $533,268

Issue Date FY: 2023 ( Subtotal = $402,857 )
2023	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	3	12/20/2022	NON-COMPETING CONTINUATION	$362,571
2023	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	001	3	1/18/2023	NON-COMPETING CONTINUATION	$40,286
														Subtotal = $402,857

Issue Date FY: 2022 ( Subtotal = $414,483 )
2022	2022	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	2	12/22/2021	NON-COMPETING CONTINUATION	$373,034
2022	2022	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	001	2	4/20/2022	NON-COMPETING CONTINUATION	$41,449
														Subtotal = $414,483

Issue Date FY: 2021 ( Subtotal = $402,857 )
2021	2021	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	1	12/30/2020	NEW	$402,857
														Subtotal = $402,857

Grand Total All Awards = $1,753,465

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Repurposing an FDA approved Drug, B-Raf Kinase Inhibitor Dabrafenib for Protection from Cisplatin- and Noise- induced Hearing Loss

Award Number: R01DC018850

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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