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Prevention of Cisplatin-induced Hearing Loss in Children with Cancer

预防癌症儿童顺铂引起的听力损失

基本信息

批准号：
10447944
负责人：
Etan Orgel
金额：
$ 4.81万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447944
关键词：
Acetylcysteine Achievement Address Aftercare Audiology Behavioral Biological Brain Cancer Control Cancer Etiology Cancer Survivor Child Childhood Cisplatin Clinical Investigator Clinical Research Clinical Trials Cochlea Communication Country Data Dose Drug Kinetics Drug usage Environment Family Fostering Free Radicals Germ Cells Growth Head Hearing Hearing Protection Hearing Tests Institution Laboratories Lead Learning Liver Malignant Childhood Neoplasm Malignant Neoplasms Mentors Mentorship Modeling Neurocognitive Deficit Pediatric Oncology Peripheral Pharmaceutical Preparations Pharmacogenomics Physiological Physiology Population Prevention Public Health Quality of life Records Research Research Design Research Proposals Sulfhydryl Compounds Survivors Testing Toxic effect Training Translational Research Xenograft Model bone cancer diagnosis chemotherapy childhood cancer survivor cisplatin induced hearing loss cohort design early phase clinical trial efficacy testing experience hearing impairment improved insight laboratory development otoprotectant ototoxicity permanent hearing loss phase III trial pre-clinical prevent prevent hearing loss progressive hearing loss tumor

项目摘要

Cisplatin is used in the treatment of many childhood cancers including brain, bone, germ cell, liver, and peripheral nervous tumors; together, these cancers constitute nearly 40% of the childhood cancers diagnosed each year. While effective for cure, cisplatin causes severe, permanent, and progressive hearing loss from theorized free-radical damage to the cochlea. This, in turn, results in debilitating neurocognitive deficits and impacts the quality of life for childhood cancer survivors. Current strategies to protect hearing are ineffective, toxic, unsafe, or inadequate. The scientific objective of this proposal is to address this need by transitioning the promising new otoprotectant drug N-acetylcysteine (NAC) into clinical trials. Pre-clinical evidence for NAC demonstrates the potential for greater efficacy than previously tested agents without compromising cisplatin efficacy. We therefore propose to test NAC in an early phase clinical trial for children receiving cisplatin to evaluate dose, toxicity, and any signs of interference with chemotherapy efficacy (Aim 1). Supporting laboratory aims on the proposed trial will provide new insight into the intersection of pharmacogenomics, pharmacokinetics, and the mechanisms of ototoxicity and otoprotection (Aim 2). Evidence for successful hearing protection will be explored through comparison to a non-NAC treated cohort and via comprehensive post-treatment physiological and behavioral hearing assessments in survivors (Aim 3). The richness of data derived from the trial will provide the basis for a subsequent Phase III trial testing efficacy as an otoprotectant. The training objectives embedded within the clinical trial will foster Dr. Orgel’s growth as a clinical investigator in cancer control focused on translational research for otoprotection. Using a combination of classroom and hands-on experience, the study will promote his proficiency with (1) study design questions surrounding otoprotection, (2) laboratory models of otoprotection and ototoxicity, and (3) audiology physiology and assessment. Dr. Orgel has access to a rich academic research environment, one of the largest pediatric oncology populations in the country, the support of his institution, and a mentorship team of renowned experts. Dr. Freyer, with extensive expertise in otoprotection in cancer trials will lead the mentoring committee consisting of (1) Dr. Neuwelt – xenograft models of ototoxicity and thiol otoprotection, including the laboratory development of NAC, (2) Dr. Eisenberg – pediatric clinical and research audiology, and representing access to the combined wealth of audiology expertise at the USC Caruso Family Center for Childhood Communication, and (3) Dr. Wayne (the Division Head for Dr. Orgel) – general translational research involving biological targets. While all mentors have long track records of mentorship, Drs. Freyer and Wayne will be primarily responsible to guide Dr. Orgel’s achievement of the milestones necessary for transition to independence. In summary, this proposal meets a critical need for finding an effective otoprotectant and provides Dr. Orgel with a robust training platform for a clear path to a R01-level competitive application and research independence.

顺铂用于治疗许多儿童癌症，包括脑癌、骨癌、生殖细胞癌、肝癌和周围神经肿瘤；这些癌症加在一起，占确诊的儿童癌症的近40% 每年。虽然顺铂对治愈有效，但它会导致严重的、永久性的和进行性的听力损失，理论上认为是自由基对耳蜗骨的损伤。这反过来又会导致衰弱的神经认知缺陷和影响儿童癌症幸存者的生活质量。目前保护听力的策略是无效的，有毒的、不安全的或不充分的这项提议的科学目标是通过过渡来满足这一需求前景看好的耳保护新药N-乙酰半胱氨酸(NAC)进入临床试验。NAC的临床前证据展示了在不影响顺铂的情况下，比之前测试的药物具有更高疗效的潜力功效。因此，我们建议在接受顺铂治疗的儿童的早期临床试验中测试NAC 评估剂量、毒性和任何干扰化疗效果的迹象(目标1)。支座针对拟议试验的实验室将为药物基因组学的交叉提供新的见解，药代动力学，以及耳毒性和耳保护机制(目标2)。成功的证据听力保护将通过与未接受NAC治疗的队列进行比较并通过全面的幸存者治疗后的生理和行为听力评估(目标3)。数据的丰富程度该试验将为随后的第三阶段试验提供基础，以测试其作为耳保护剂的有效性。临床试验中嵌入的培训目标将促进奥格尔博士作为临床医生的成长癌症控制领域的研究人员专注于耳保护的转译研究。使用以下组合课堂和实践经验，学习将促进他熟练使用(1)学习设计问题周围耳保护，(2)耳保护和耳毒性的实验室模型，以及(3)听力生理学和评估。奥尔格尔医生拥有丰富的学术研究环境，是世界上最大的儿科美国的肿瘤学人口，他的机构的支持，以及一个由知名专家组成的指导团队。在癌症试验中拥有丰富的耳防护专业知识的Freyer博士将领导指导委员会。包括：(1)NeuWelt博士-异种耳毒性和硫醇耳防移植模型，包括实验室 NAC的发展，(2)Eisenberg博士-儿科临床和研究听力学，并代表访问南加州大学卡鲁索家庭儿童交流中心拥有丰富的听力学专业知识，和(3)韦恩博士(奥格尔博士的部门负责人)--涉及生物学的一般翻译研究目标。虽然所有导师都有长期的导师记录，但Freyer博士和Wayne博士将主要负责指导奥格尔博士完成向独立过渡所需的里程碑。在……里面综上所述，这项建议满足了寻找有效的耳保护剂的迫切需要，并为奥格尔博士提供了一个强大的培训平台，为R01级别的竞争性应用和研究独立开辟了一条清晰的道路。