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

项目总结/文摘

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.