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

重新利用 FDA 批准的 MEK 抑制剂 Trametinib 以预防顺铂引起的听力损失

• 批准号: 10389136
• 负责人: Matthew A Ingersoll
• 金额: $ 6.64万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2025-02-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389136
• 关键词: Repurposing; FDA; Approved; MEK; Inhibitor

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.

项目概要/摘要 40-60% 的化疗患者因顺铂耳毒性导致听力损失，导致听力下降 生活质量和令人衰弱的语言障碍，但尚未获得食品和药物管理局 (FDA) 批准 目前可以治疗。目前临床前和临床试验中的化合物仅提供部分 保护或与危及生命的副作用相关，因此显然需要替代治疗 战略。最近，发现 BRAF 抑制剂达拉非尼 (dabrafenib) 在体内可防止顺铂毒性 以临床相关剂量施用。其他丝裂原激活蛋白激酶 (MAPK) 抑制剂 途径，包括 MEK 抑制剂曲美替尼 (Trametinib)，也可以保护耳蜗外植体模型免受顺铂毒性。 重要的是，达拉非尼和曲美替尼的组合已获得 FDA 批准用于治疗黑色素瘤，并且可能 快速治疗顺铂引起的听力损失。这些化合物也能有效对抗大脑 转移，揭示它们穿过血脑屏障，这类似于血液迷宫屏障 耳朵。因此，我们假设曲美替尼将在体内预防顺铂诱导的耳毒性，并且 与达拉非尼联合使用可提供增强的保护。在目标 1 中，我们将确定 MEK 是否 抑制剂曲美替尼（Trametinib）可在小鼠模型中防止顺铂诱导的耳毒性。我们将测试是否 口服曲美替尼使用临床相关的多剂量、多剂量减轻 CBA 小鼠模型中的顺铂耳毒性 循环治疗模型。听力损失将通过测量听觉脑干反应（ABR）和 畸变产物耳声发射 (DPOAE) 阈值变化，以及形态学分析 耳蜗 HC、支持细胞、血管纹和 SGN。曲美替尼介导的 MAPK 通路的验证 通过对成年小鼠耳蜗进行免疫染色来获得抑制作用。确认曲美替尼跨越 通过上述免疫染色和质谱（LC-MS）实现血迷路屏障 来自曲美替尼治疗小鼠的外淋巴样本。在目标 2 中，确定曲美替尼 (Trametinib) 和 达拉非尼可增强对顺铂引起的耳毒性的保护 我们将测试药物组合的 防止耳毒性、调节 MAPK 通路以及穿过血迷路屏障的能力 目标 1 中描述。这项研究将是第一个研究曲美替尼 (Trametinib) 及其组合的潜力的研究 曲美替尼 (trametinib) 与达拉非尼 (dabrafenib)，用于预防顺铂引起的听力损失，因为我们寻求提供强大的 目前尚无 FDA 批准的治疗方法的疾病的候选治疗药物。此外，克赖顿还举办了 7 定期在项目、联席会议和研讨会上进行合作的听觉研究实验室。此外， 克赖顿的转化听力中心被授予 NIH 附属生物医学研究中心 卓越 (COBRE) 资助将基本听力损失研究转化为实用疗法。它将允许 扩大核心设施设备并招募新的研究人员。因此，Creighton 提供了 为寻求在听觉研究领域发展事业的初级科学家提供良好的环境和支持。