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时期癌症，包括脑，骨，生殖细胞，肝脏和周围神经肿瘤；这些癌症共同构成了诊断的童年癌症的几乎40％每年。虽然有效治愈，但顺铂会导致严重，永久和进行性听力损失理论上对耳蜗的自由基损害。反过来，这导致神经认知缺陷和影响儿童癌症生存的生活质量。当前保护听力的策略无效，有毒，不安全或不足。该提议的科学目标是通过过渡来满足这一需求有希望的新的耳肠药物N-乙酰半胱氨酸（NAC）进入临床试验。 NAC的临床前证据证明了比以前测试的药物更高的效率的潜力，而不会损害顺铂功效。因此，我们建议在早期临床试验中测试NAC，以使接受顺铂的儿童评估剂量，毒性和干扰化学疗法效率的任何迹象（AIM 1）。支持实验室针对拟议的试验的目标将为药物基因组学的交集提供新的见解，即药代动力学以及耳毒性和耳牙的机制（AIM 2）。成功的证据听力保护将通过与非NAC治疗的队列进行比较，并通过综合治疗后的生理和行为听力听力评估在生存中（AIM 3）。数据丰富从试验中得出的将为后续III期试验测试效率作为治疗剂提供基础。临床试验中嵌入的培训目标将促进Orgel博士作为临床的成长癌症控制研究人员的重点是转化研究。结合教室和动手经验，这项研究将通过（1）学习设计问题来促进他的熟练程度周围的Otoprotection，（2）耳毒性和耳毒性的实验室模型，以及（3）发烧生理学和评估。 Orgel博士可以使用丰富的学术研究环境，这是最大的儿科之一该国的肿瘤学人群，其机构的支持以及著名专家的心态团队。 Freyer博士，在癌症试验中具有广泛的Otoprotection专业知识，将领导心理委员会由（1）Neuwelt博士组成 - 耳毒性和硫醇奥托保护的异种移植模型，包括实验室 NAC的开发，（2）Eisenberg博士 - 儿科临床和研究听力学，代表进入 USC Caruso儿童交流中心的大量音频专业知识，（3）Wayne博士（Orgel博士的部门负责人） - 一般翻译研究，涉及生物学目标。尽管所有导师都有长期的指导记录，但博士。弗雷尔和韦恩将是主要的负责指导Orgel博士实现过渡到独立所必需的里程碑。总而言之，该建议满足寻找有效的环绕剂的关键需求，并为Orgel博士提供一个强大的培训平台，可通向R01级竞争应用和研究独立性。