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

• 批准号: 9108770
• 负责人: Etan Orgel
• 金额: $ 19.56万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108770
• 关键词: Acetylcysteine; Achievement; Address; Adult; Aftercare; Animals; Antioxidants; Attenuated; Audiology; Audiometry; Award; Behavioral; Biological; Brain; Cancer Etiology; Cancer Survivor; Chemotherapy-Oncologic Procedure; Child; Childhood; Cisplatin; Clinical Investigator; Clinical Research; Clinical Trials; Cochlea; Communication; Complex; Country; Data; Disease; Dose; Dose-Limiting; Drug Kinetics; Drug usage; Enrollment; Environment; Family; Fostering; Free Radicals; Genetic Markers; Genetic Polymorphism; Germ Cells; Germ cell tumor; Glutathione; Glutathione S-Transferase; Goals; Growth; Head; Hearing; Hearing Tests; Image; Infusion procedures; Institution; Intravenous; Kinetics; Laboratories; Language; Lead; Learning; Liver; Liver neoplasms; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Mentors; Mentorship; Modeling; Monitor; Neuroblastoma; Neurocognitive Deficit; Outcome; Oxidants; Pathology; Pathway interactions; Pediatric Oncology; Peripheral; Pharmaceutical Preparations; Pharmacogenomics; Phase; Physiological; Physiology; Plasma; Population; Prevalence; Prevention; Public Health; Quality of life; Rattus; Records; Regimen; Research; Research Design; Research Proposals; Risk; Rodent Model; Safety; Sampling; Serum; Socialization; Sulfhydryl Compounds; Survivors; Testing; Toxic effect; Training; Translational Research; Tumor Markers; Xenograft Model; base; bone; cancer diagnosis; cancer therapy; chemotherapy; childhood cancer survivor; cohort; design; efficacy testing; experience; hearing impairment; improved; insight; laboratory development; meetings; osteosarcoma; otoacoustic emission; ototoxicity; phase III trial; pre-clinical; prevent; public health relevance; response; tumor

 DESCRIPTION (provided by applicant): 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, toxiciy, 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 caner 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) animal xenograft 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.

 描述（由申请人提供）：顺铂用于治疗许多儿童癌症，包括脑肿瘤、骨肿瘤、生殖细胞肿瘤、肝癌和周围神经肿瘤；这些癌症在每年诊断的儿童癌症中占近 40%。为了治愈，顺铂会因理论上的耳蜗自由基损伤而导致严重、永久性和进行性听力损失，这反过来会导致神经认知缺陷并影响生活质量。该提案的科学目标是通过将有前途的新型耳保护药物 N-乙酰半胱氨酸（NAC）转入临床试验来满足这一需求。 - NAC 的临床证据表明其具有更大功效的潜力 因此，我们建议在接受顺铂的儿童的早期临床试验中测试 NAC，以评估剂量、毒性以及干扰化疗疗效的任何迹象（目标 1）。试验将为药物基因组学、药代动力学以及耳毒性和耳保护机制的交叉提供新的见解（目标 2）将通过与试验进行比较来探索成功听力保护的证据。对非 NAC 队列进行治疗，并通过对幸存者进行全面的治疗后生理和行为听力评估（目标 3）。从试验中获得的丰富数据将为随后的 III 期试验测试作为耳保护剂的功效提供基础。嵌入临床试验将促进 Orgel 博士成长为癌症控制领域的临床研究者，专注于耳保护的转化研究。该研究结合课堂和实践经验，将提高他对 (1) 研究设计问题的熟练程度。 Orgel 博士拥有丰富的学术研究环境、美国最大的儿科肿瘤学群体之一以及其机构的支持。以及由在癌症试验中的耳保护方面拥有广泛专业知识的著名专家组成的指导团队将领导指导委员会，该委员会由 (1) Neuwelt 博士 - 异种移植模型组成。耳毒性和硫醇耳保护，包括 NAC 的实验室开发，(2) Eisenberg 博士 - 儿科临床和研究听力学，并代表获得南加州大学卡鲁索家庭儿童交流中心丰富的听力学专业知识，以及 (3) 博士韦恩（奥格尔博士的部门负责人）——一般转化研究生物学目标虽然所有涉及的导师都有长期的指导记录，但弗雷耶和韦恩博士将主要负责指导奥格尔博士。 Orgel 实现了向独立过渡所需的里程碑总而言之，该提案满足了寻找有效耳保护剂的迫切需求，并为 Orgel 博士提供了强大的培训平台，为 R01 级竞争性应用和研究独立性提供了明确的道路。