Prevention of Cisplatin-induced Hearing Loss in Children with Cancer

顺铂用于治疗许多儿童癌症，包括脑癌、骨癌、生殖细胞癌、肝癌和乳腺癌。 周围神经肿瘤;这些癌症占诊断的儿童癌症的近40% 每年.虽然顺铂对治愈有效，但顺铂会导致严重的，永久性的和进行性的听力损失， 自由基对耳蜗的损伤这反过来又会导致神经认知缺陷， 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、不安全或不适当。该提案的科学目标是通过过渡来满足这一需求 有前途的新型耳保护药物N-乙酰半胱氨酸（NAC）进入临床试验。NAC的临床前证据 证明了在不损害顺铂的情况下，比先前测试的药物具有更大疗效的潜力 功效因此，我们建议在接受顺铂的儿童的早期临床试验中测试NAC， 评价剂量、毒性和干扰化疗疗效的任何体征（目的1）。支持 实验室的目标是对拟议的试验将提供新的洞察力的交叉药物基因组学， 药代动力学以及耳毒性和耳保护机制（目的2）。成功的证据 将通过与非NAC治疗队列的比较以及通过全面的 幸存者的治疗后生理和行为听力评估（目标3）。数据的丰富性 将为随后的III期试验测试作为耳保护剂的功效提供基础。 临床试验中嵌入的培训目标将促进Orgel博士作为临床医生的成长 癌症控制研究者集中于耳保护转化研究。结合使用 课堂和实践经验，这项研究将促进他的熟练程度与（1）研究设计问题 周围的耳保护，（2）耳保护和耳毒性的实验室模型，和（3）听力生理学 和评估。Orgel博士拥有丰富的学术研究环境，是世界上最大的儿科研究机构之一。 这得益于他所在机构的支持，以及知名专家的指导团队。 博士Freyer在癌症试验中的耳保护方面具有广泛的专业知识，将领导指导委员会 包括（1）Neuwelt博士-耳毒性和巯基耳保护的异种移植模型，包括实验室 NAC的发展，（2）艾森伯格博士-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）-涉及生物学的一般转化研究 目标的虽然所有的导师都有长期的指导记录，但弗莱尔和韦恩博士将主要 负责指导Orgel博士实现向独立过渡所需的里程碑。在 总之，该建议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。

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.