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.
The chemotherapy agent cisplatin is important for cure of many childhood cancers but causes permanent hearing loss in up to two-thirds of the children who survive their cancer. This research proposal is designed to test a promising new use for the drug N-Acetylcysteine (NAC) to prevent this chemotherapy-induced hearing loss and learn more about how cisplatin damages hearing. Preventing hearing loss from cisplatin will have significant bearing on public health by markedly improving the everyday quality of life for the growing numbers of children now surviving cancer.
