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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要由顺铂毒性引起的听力损失会影响40-60％的化学疗法患者，导致下降生活质量和令人衰弱的语言障碍，但没有食品药品管理局（FDA）批准目前可获得治疗。临床前和临床试验中的当前化合物仅提供部分保护或与威胁生命的副作用有关，因此有明显的需要替代治疗战略。最近，发现BRAF抑制剂dabrafenib在体内免受顺铂的毒性保护以临床相关剂量进行管理。有丝分裂原激活蛋白激酶（MAPK）的其他抑制剂包括MEK抑制剂Trametinib在内的途径也可以免受人工耳蜗模型中的顺铂毒性。重要的是，dabrafenib和trametinib的组合是FDA批准的，用于治疗黑色素瘤，可能快速跟踪以进行顺铂诱导的听力损失。这些化合物也对大脑有效转移，揭示它们越过了与血脑屏障相似的血脑屏障耳朵。因此，我们假设曲线替尼将防止顺铂诱导的体内毒性和与Dabrafenib结合使用增强的保护。在AIM 1中，我们将确定MEK是否抑制剂Trametinib承认在小鼠模型中抗铂诱导的耳毒性的保护。我们将测试是否口服Trametinib使用临床上相关的多剂量多剂量多剂量，多剂量多剂量，在CBA小鼠模型中减轻顺铂耳毒性循环处理模型。听力损失将通过测量听觉脑干响应（ABR）和失真产物耳声发射（DPOAE）阈值移位，以及形态学分析人工耳蜗HC，支持细胞，血管和SGNS。曲线替尼介导的MAPK途径的验证通过对成年小鼠耳蜗进行免疫染色，将获得抑制作用。确认trametinib穿过上述免疫染色和质谱（LC-MS）实现的血液临床屏障来自曲美替尼治疗的小鼠的perilymph样品。在AIM 2中，确定曲妥尼和 dabrafenib提供了增强的防止顺铂诱导的耳毒性的保护，我们将测试该药物组合的防止耳毒性，对MAPK途径的调节以及越过血液临床障碍的能力在AIM 1中描述。这项研究将是第一个研究Trametinib的潜力的研究，并将与dabrafenib一起进行曲敏替尼，以防止顺铂引起的听力损失，因为我们寻求提供强大的目前未经FDA批准治疗的疾病的治疗候选者。此外，Creighton主持7 听觉研究实验室定期在项目，联合会议和半段中合作。此外， Creighton的翻译听证中心已获得NIH附属生物医学研究中心卓越（COBRE）赠款将基本的听力损失研究转化为实际疗法。它将允许核心设施设备的扩展以及招募新的研究学院。那，克雷顿提供了优秀的环境和对试图在听觉研究领域建立职业的初级科学家的支持。