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Repurposing FDA-Approved MEK Inhibitor Trametinib for Protection Against Cisplatin-Induced Hearing Loss

Award Number: F32DC020102
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/10/2022
PERIOD OF PERFORMANCE END DATE: 10/27/2023

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Repurposing FDA-Approved MEK Inhibitor Trametinib for Protection Against Cisplatin-Induced Hearing Loss - Project Summary/Abstract Hearing loss caused by cisplatin ototoxicity affects 40-60% of chemotherapy patients resulting in decreased quality-of-life and debilitating language barriers, yet no Food and Drug Administration (FDA)-approved treatment is currently available. Current compounds in preclinical and clinical trials provide only partial protection or are associated with life-threatening side effects, thus there is a clear need alternative treatment strategy. Recently, BRAF inhibitor dabrafenib was found to protect from cisplatin toxicity in vivo when administered at clinically relevant doses. Additional inhibitors of the mitogen-activated protein kinase (MAPK) pathway, including MEK inhibitor trametinib, also protect from cisplatin toxicity in cochlear explant models. Importantly, a combination of dabrafenib and trametinib is FDA-approved for treatment of melanoma and may be fast-tracked for treatment cisplatin-induced hearing loss. The compounds are also effective against brain metastases, revealing they cross the blood-brain barrier which is similar to the blood-labyrinth barrier in the ear. We therefore hypothesize trametinib will protect against cisplatin-induced ototoxicity in vivo and provide enhanced protection in combination with dabrafenib. In aim 1, we will determine whether MEK inhibitor trametinib confers protection from cisplatin-induced ototoxicity in mouse models. We will test whether oral trametinib mitigates cisplatin ototoxicity in CBA mouse models using a clinically relevant multi-dose, multi- cycle treatment model. Hearing loss will be determined by measuring auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) threshold shifts, along with morphological analysis of cochlear HCs, supporting cells, stria vascularis, and SGNs. Verification of trametinib-mediated MAPK pathway inhibition will be obtained by immunostaining of adult mouse cochleae. Confirmation trametinib crosses the blood-labyrinth barrier achieved by above mentioned immunostaining and Mass Spectrometry (LC-MS) of perilymph samples from trametinib treated mice. In aim 2, determine if a combination of trametinib and dabrafenib provide enhanced protection from cisplatin-induced ototoxicity We will test the drug combination’s protection from ototoxicity, regulation of the MAPK pathway, and ability to cross the blood-labyrinth barrier as described in aim 1. This study will be the first to investigate the potential of trametinib, and combination of trametinib with dabrafenib, for protection against cisplatin-induced hearing loss as we seek to provide a robust therapeutic candidate for a disorder with no current FDA-approved treatment. Moreover, Creighton hosts 7 auditory research labs who regularly collaborate on projects, joint meetings, and seminars. Additionally, Creighton’s Translational Hearing Center has been awarded an NIH-affiliated Centers of Biomedical Research Excellence (COBRE) grant to translate basic hearing loss research into practical therapies. It will allow for expansion of core facility equipment as well as recruit new research faculty. Thus, Creighton provides an excellent environment and support for junior scientists seeking to build a career in the auditory research field.


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 = -$17,135 )
2024	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	001	2	8/22/2024	NON-COMPETING CONTINUATION	$0
2024	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	2	1/12/2024	NON-COMPETING CONTINUATION	-$17,135
														Subtotal = -$17,135

Issue Date FY: 2023 ( Subtotal = $71,792 )
2023	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	001	2	2/7/2023	NON-COMPETING CONTINUATION	$1,990
2023	2023	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	2	1/12/2023	NON-COMPETING CONTINUATION	$69,802
														Subtotal = $71,792

Issue Date FY: 2021 ( Subtotal = $66,390 )
2021	2021	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	001	1	8/13/2021	NEW	$0
2021	2021	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	000	1	8/13/2021	NEW	$66,390
														Subtotal = $66,390

Grand Total All Awards = $121,047

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Repurposing FDA-Approved MEK Inhibitor Trametinib for Protection Against Cisplatin-Induced Hearing Loss

Award Number: F32DC020102

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/10/2022

PERIOD OF PERFORMANCE END DATE: 10/27/2023

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