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、骨、生殖细胞、肝和周围神经肿瘤;这些癌症一起构成每年诊断的儿童癌症的近40%。虽然顺铂对治愈有效，但由于理论上的自由基对耳蜗的损伤，顺铂会导致严重的、永久性的和进行性的听力损失。这反过来又会导致神经认知缺陷，并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。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）过渡到临床试验来解决这一需求。NAC的临床前证据证明了更大疗效的潜力 而不影响顺铂的疗效。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、毒性和任何干扰化疗疗效的迹象（目的1）。支持拟议试验的实验室目标将为药物基因组学、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）。将通过与非NAC治疗队列进行比较，并通过对幸存者进行全面的治疗后生理和行为听力评估，探索成功听力保护的证据（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。临床试验中的培训目标将促进Orgel博士作为癌症控制临床研究者的成长，专注于耳保护的转化研究。结合课堂和实践经验，本研究将提高他在以下方面的熟练程度：（1）围绕耳保护的研究设计问题，（2）耳保护和耳毒性的动物异种移植模型，以及（3）听力学生理学和评估。Orgel博士拥有丰富的学术研究环境，全国最大的儿科肿瘤学人群之一，他所在机构的支持，以及知名专家的指导团队。Freyer博士在癌症试验中的耳保护方面拥有丰富的专业知识，将领导指导委员会，该委员会由（1）Neuwelt博士-耳毒性和巯基耳保护的异种移植模型，包括NAC的实验室开发，（2）Eisenberg博士-儿科临床和研究听力学，并代表南加州大学卡鲁索家庭儿童交流中心的听力学专业知识，和（3）韦恩博士（Orgel博士的部门负责人）-涉及生物靶点的一般转化研究。虽然所有导师都有长期的导师记录，但Freyer博士和韦恩博士将主要负责指导Orgel博士实现向独立过渡所需的里程碑。总之，该提案满足了寻找有效耳保护剂的关键需求，并为Orgel博士提供了一个强大的培训平台，为R 01级竞争性应用和研究独立性提供了明确的途径。