| According to the World Health Organization, around 466 million people worldwide have disabling hearing loss, a number the organization projects will double by 2050 to affect 1 in 10 people. However, a groundbreaking Creighton University School of Medicine study has identified a drug that has the potential to protect against or treat hearing loss in humans. The findings are significant because no such FDA-approved drug currently exists, and the drug that has shown effectiveness to protect hearing in animal models in the study, dabrafenib, is an FDA-approved drug that is currently used in treating cancers. Repurposing FDA-approved drugs is an attractive and effective alternative because it can significantly reduce the development timeline (by up to 5 to 8 years) and cost (by up to 40%) of making them available to the public compared to new chemical compounds. Permanent hearing loss is a major side effect cancer patients experience after undergoing cisplatin chemotherapy, affecting 40% to 60% of people who receive the treatment. Dabrafenib is a medication that can be taken orally to combat cancers with an activated gene called BRAF, such as melanoma, small-cell lung carcinoma, and thyroid and biliary tract cancers. In a paper published by Science Advances, Creighton scientists and students involved in the research found that dabrafenib can be repurposed to prevent cisplatin- and noise-induced hearing loss in mice. Six other drugs in the BRAF signaling pathway also showed significant protection from cisplatin-induced cell loss. Since dabrafenib has already gone through cancer clinical trials in humans and its side effects are known and relatively minimal, it is a good candidate to advance through hearing clinical trials, said Tal Teitz, PhD, an assistant professor in Creighton University’s Department of Pharmacology and Neuroscience, School of Medicine, the group leader and corresponding author of the study. “There are many types of hearing loss that are caused by cisplatin treatment, noise exposure, antibiotics and aging. Our idea was that there could be some common cellular pathways between these different forms of hearing loss,” Teitz said. “It’s very exciting that we were able to identify a drug that was effective in protecting against noise- and cisplatin-induced hearing loss. The cellular pathway BRAF/MEK/ERK we are targeting in this study is known to enhance cell growth in proliferating tumor cells, but interestingly when inhibited, it can protect from death in the non-dividing cells in the ear.” According to Matthew Ingersoll, PhD, the first author of the paper and a postdoctoral fellow who handled the day-to-day experimental work in the laboratory, the study demonstrated that when dabrafenib is given orally to mice receiving cisplatin, it inhibits the BRAF kinase pathway to provide hearing protection by preventing the death of cells in the inner ear. Hearing protection also occurred in mouse cochlear explants pretreated with dabrafenib an hour before receiving cisplatin treatment. “Dabrafenib showed no adverse effect to cisplatin’s tumor-killing ability in tumor cell lines, and from having previously gone through the FDA approval process, we already know that some of the possible side effects of the drug such as headaches and skin rash are manageable, especially when the drug is administered for short periods of time,” Ingersoll said. The study also tested whether dabrafenib protects from noise-induced hearing loss. Before exposing mice to 100 decibels (the noise level typical of a running lawnmower) for two hours – enough to cause permanent hearing loss – they were treated with dabrafenib. Significant hearing protection was achieved. Since noise exposure is often unpredictable, the study also examined if dabrafenib could provide hearing protection after damaging noise exposure. Mice were given dabrafenib treatment starting 24 hours after noise exposure, administered alone and in combination with the compound AZD5438, another oral drug the group identified for hearing protection. The drugs demonstrated hearing protection in mice after noise exposure, and full protection was achieved with the drug combination. “What makes dabrafenib a particularly promising candidate is that it can be taken orally – the least invasive and most cost-effective mode of treatment,” Ingersoll said. “Existing surgical treatments for hearing loss like cochlear implants are highly invasive and expensive.” Teitz said the promising results will lead to more preclinical studies that test the effectiveness of dabrafenib when mice receive lower doses of cisplatin treatment for a longer period of time, and also receive dabrafenib in lower doses for a similar longer period. “This will better mimic what we do in clinics because patients usually receive cisplatin in a few cycles, which consists of treatment every day for one week, followed by three weeks with no chemotherapy,” Teitz said. “In this study, we gave one large dose of cisplatin, so we also want to test the effectiveness in mice receiving smaller doses of cisplatin over few cycles in a 60-day period. We will also test lower doses of dabrafenib – the lower we can get the dose, the better it will be tolerated by patients treated with cisplatin. Dabrafenib may also be helpful for overcoming side effects of cisplatin chemotherapy in other organs in the body, such as the kidneys and brain, and our research group is currently exploring this further.” Ingersoll emphasized that while the research findings are based on preliminary animal studies, he said it is an exciting development in the field of hearing. “More studies need to be done, but we are very excited about continuing to study this drug and understand more about its efficacy and how it works to treat hearing loss,” Ingersoll said. “It is incredibly promising research, and I am hopeful it can be used in the future to improve the quality of life for people affected by hearing loss.” The study is a continuation of research Teitz conducted in the Department of Developmental Neurobiology at St. Jude Children’s Research Hospital with Jian Zuo, PhD, to develop studies on drug therapy for hearing loss. Zuo is now chair of the Department of Biomedical Sciences and professor in Creighton University’s School of Medicine. Creighton and St. Jude worked collaboratively on the study, using St. Jude’s high-throughput screens to identify small molecules that allow protection against cisplatin toxicity, where dabrafenib was identified as a “top hit,” or good therapeutic target. Taosheng Chen, PhD; Jaeki Min, PhD; and Duane Currier, PhD from St. Jude contributed to the drug screens performed in the study. David Z.Z. He, PhD; Huizhan Liu, PhD; Zhenhang Xu, PhD; and Marisa Zallocchi, PhD, from Creighton University contributed their expertise to the research. A Creighton graduate, Emma Malloy (now a Creighton medical student), and two undergraduate Creighton students in Teitz’s Lab – Lauryn Caster and Eva Holland – contributed research to the study through the University’s Center for Undergraduate Research and Scholarship (CURAS) program and Summer Research program. Caster and Holland have also since been accepted to Creighton University’s School of Medicine. The study was funded by research grants from the National Institutes of Health, state of Nebraska, Bellucci Translational Hearing Research Foundation, Office of Naval Research, ALSAC, Dialysis Clinic Inc., Dr. and Mrs. R. Ferlic Research Undergraduate Fellowship and the American Hearing Research Foundation. |
