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: 10552555
• 负责人: Matthew A Ingersoll
• 金额: $ 5.47万
• 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 2023-10-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552555
• 关键词: Adult; Affect; Antineoplastic Agents; Auditory; Auditory Brainstem Responses; Award; BRAF gene; Blood; Cell Line; Cell physiology; Cells; Centers of Research Excellence; Cisplatin; Clinical Trials; Cochlea; Collaborations; Core Facility; Data; Disease; Disease remission; Dose; Drug Combinations; Ear; Environment; Equipment; Grant; Hair Cells; Hearing; Inbred CBA Mice; Individual; Joints; Laboratories; Labyrinth; Language; Language Development; Life; MEKs; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Metastatic malignant neoplasm to brain; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Modeling; Morphology; Mus; Neurons; Oral; Pathway interactions; Patients; Perilymph; Phosphorylation; Play; Protein Kinase; Quality of life; Regulation; Research; Role; Sampling; Scientist; Spectrometry; Stria Vascularis; Supporting Cell; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; Translating; Tumor Promotion; United States Food and Drug Administration; United States National Institutes of Health; Work; Zebrafish; alternative treatment; anti-cancer; blood-brain barrier crossing; cancer therapy; career; chemotherapeutic agent; chemotherapy; cisplatin induced hearing loss; clinically relevant; drug testing; hearing impairment; in vivo; inhibitor; kinase inhibitor; meetings; melanoma; mouse model; novel; otoacoustic emission; ototoxicity; preclinical trial; prevent; recruit; research faculty; side effect; spiral ganglion; therapeutic candidate; therapeutic target; treatment strategy; tumor

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.

项目总结/摘要 顺铂耳毒性引起的听力损失影响40-60%的化疗患者， 生活质量和语言障碍，但没有食品和药物管理局（FDA）批准 治疗目前可用。目前在临床前和临床试验中的化合物仅提供了部分 保护或与危及生命的副作用有关，因此显然需要替代治疗 战略最近，发现BRAF抑制剂达拉菲尼在体内保护顺铂毒性， 以临床相关剂量给药。丝裂原活化蛋白激酶（MAPK）的其他抑制剂 包括MEK抑制剂曲美替尼在内的其他药物也可以在耳蜗外植体模型中保护顺铂毒性。 重要的是，达拉非尼和曲美替尼的组合被FDA批准用于治疗黑色素瘤，并且可以 快速追踪治疗顺铂引起的听力损失。这些化合物对大脑也有效 转移，揭示它们穿过血脑屏障，这类似于脑转移中的血迷路屏障。 耳朵因此，我们假设曲美替尼在体内可预防顺铂诱导的耳毒性， 与达拉非尼组合提供增强的保护。在目标1中，我们将确定MEK是否 抑制剂曲美替尼在小鼠模型中提供保护以免受顺铂诱导的耳毒性。我们将测试 在CBA小鼠模型中，口服曲美替尼可减轻顺铂的耳毒性， 循环治疗模式听力损失将通过测量听性脑干反应（ABR）来确定， 畸变产物耳声发射（DPOAE）阈值漂移，沿着与形态学分析， 耳蜗毛细胞、支持细胞、血管纹和SGN。曲美替尼介导的MAPK通路的验证 通过成年小鼠耳蜗的免疫染色获得抑制。确认曲美替尼穿过 通过上述免疫染色和质谱法（LC-MS）获得的血迷路屏障 来自曲美替尼处理的小鼠的外淋巴样品。在目标2中，确定曲美替尼和 达拉非尼对顺铂诱导的耳毒性具有增强的保护作用 保护耳毒性，调节MAPK通路，以及穿越血迷路屏障的能力， 目标1所述。这项研究将是第一个调查曲美替尼的潜力，以及联合 曲美替尼与达拉非尼，用于预防顺铂引起的听力损失，因为我们寻求提供一个强大的 目前没有FDA批准的治疗方法的疾病的治疗候选者。此外，克雷顿还拥有7个 听觉研究实验室，他们定期在项目、联席会议和研讨会上合作。此外，本发明还 Creighton的翻译听力中心已被授予NIH附属的生物医学研究中心 卓越（COBRE）资助将基础听力损失研究转化为实际治疗。它将允许 扩大核心设施设备以及招聘新的研究人员。因此，Creighton提供了一个 为寻求在听觉研究领域建立职业生涯的年轻科学家提供良好的环境和支持。