Chemotherapy Drug Leads to Potential Hearing Loss Breakthrough
Researchers at the Creighton University School of Medicine have identified a drug that can protect against hearing loss in mice, and they think it can work in humans, too. The best part: It’s a drug already on the market.
The findings, published in the journal Science Advances,1 are a potential breakthrough for the approximately 466 million people worldwide with disabling hearing loss.2 They focus on the use of a chemotherapy drug called Tafinlar (dabrafenib).
“We’re very excited about our initial results so far,” lead study author Matthew Ingersoll, PhD, a Creighton postdoctoral fellow, tells Verywell. “Obviously, these are in mice. However, since dabrafenib is already an FDA-approved drug, and it has very minimal side effects—skin rash is one of the worst side effects some people have—we’re hoping we can get it to clinical trials faster. I think it has a lot of applications in the future.”
What Is Dabrafenib?
Dabrafenib (brand name Tafinlar) is a type of oral chemotherapy used to treat cancers with a BRAF gene mutation. It is often used in tandem with a medication called trametinib (Mekinist) to treat melanoma.3
Types of Hearing Loss
Sometimes, hearing loss can be temporary, such as when caused by an ear infection. These cases can often be treated with antibiotics. Other times, hearing loss is permanent.
That’s because the delicate hair cells in the inner ear that help us hear don’t regenerate and can’t be repaired or replaced. Hearing aids and cochlear implants are devices that can mimic the auditory process, but presently, there are no U.S. Food and Drug Administration (FDA) approved drugs for hearing loss.
However, there are some candidate compounds in preclinical and clinical trials. Of those candidates, both sodium thiosulfate4 and the steroid dexamethasone5 have shown some moderate, though not consistent, benefits.
“Hearing loss is a really important medical need,” Tal Tietz, PhD, assistant professor at Creighton University School of Medicine’s Department of Pharmacology and Neuroscience and group study leader, tells Verywell. “Five to 10% of the population has some hearing loss caused by noise exposure, aging, and also chemotherapy.”
Five to 10% of the population has some hearing loss caused by noise exposure, aging, and also chemotherapy.
Teitz explains that it’s not completely clear why, but kidney, brain, and hair cells—including the hair cells in the ear—are more sensitive and susceptible to toxicity from the chemo drug cisplatin than other body tissues.
According to Ingersoll, it's because chemotherapy isn't designed to have specific targets.
"The thing you have to understand with chemotherapy drugs is they attack cancer cells, which are basically your cells that have just gone rogue," he says. "It’s difficult to find chemotherapy drugs that specifically target the cancer cells and don’t do damage anywhere else in the body. That’s what’s going on with cisplatin. Yes, it’s very effective at killing off the tumor cells, but it’s not very specific to those. It also harms other parts of the body, including your hearing cells.”
Previous research has found that hearing loss affects 40% to 60% of adult and pediatric patients following cisplatin chemotherapy, which is used to treat many types of solid tumorous cancers, including bladder, lung, pancreatic, testicular, neuroblastoma, and ovarian.6 Tietz, who has spent more than 25 years studying cancer, estimates cisplatin is used in about 10% to 20% of all cancer treatments, either by itself or in combination with other drugs.
A Breakthrough for Hearing Loss
Teitz has been studying cisplatin- and noise-induced hearing loss for about eight years, first at St. Jude Children’s Research Hospital and now at Creighton University. During that time, she and her colleagues have screened thousands of compounds. They focused mainly on drugs already approved by the FDA.
Repurposing FDA-approved drugs has emerged as an attractive and cost-effective strategy in medicine. The chemical compounds have already been developed and are proven safe and effective in humans, shaving years and tens or hundreds of millions of dollars off the total cost of bringing a drug to market.
Teitz and her team have found promising results with dabrafenib, a BRAF kinase protein inhibitor. The FDA approved dabrafenib in 2013 as an oral treatment for types of melanoma with a BRAF mutation.7
Dabrafenib also inhibits the BRAF kinase pathway that prevents the death of hair cells in the inner ears of mice. Six other drugs in the BRAF signaling pathway have also shown significant protection from cisplatin-induced cell loss, according to a study announcement.6
Teitz and her team gave the mice 100 mg/kg of body weight of dabrafenib, a nontoxic dosage that is comparable to the daily dose approved for humans, twice a day for three days: 45 minutes before cisplatin treatment and then 24 and 48 hours after. That was enough to see clinically significant hearing protection. The protection could be even greater when combined with other drugs.
Ingersoll is encouraged by their findings, explaining that some patients take dabrafenib for up to a year. Teitz adds because it’s well-tolerated by many, that makes it a good candidate to advance through hearing clinical trials. The fact that dabrafenib is administered orally means it’s the least invasive and most portable treatment method, offering even greater treatment potential. It’s also cost effective relative to other cancer drugs.
Most importantly, the researchers found dabrafenib does not interfere with cisplatin’s effectiveness at killing tumors and, in some cases, worked with cisplatin to increase tumor cell death. Dabrafenib also penetrates the blood-brain barrier, a major obstacle for drug development for hearing loss.
The researchers also explored whether dabrafenib could offer hearing protection after unexpected damaging noise exposure. That meant exposing the mice to two hours of noise at 100 decibels, a noise level that can cause permanent damage. Teitz describes that as the sound of a typical lawn mower running constantly. Some mice were given dabrafenib 24 hours after noise exposure, and others were given dabrafenib in combination with the oral compound AZD5438, another drug researchers identified for hearing protection. Dabrafenib alone offered mice hearing protection after noise exposure, and the mice had nearly full noise protection when combined with AZD5438.
“By combining these two drugs and seeing that they work well together, we can actually lower the dose of both of them,” Ingersoll says. “This helps reduce any side effects that the patient could possibly get, and it’s much easier on the patients.”
What This Means For You
Researchers found promising results for a drug that could prevent or reverse hearing loss caused by noise exposure or chemotherapy in mice. Further research is needed, but it could offer hope for millions of people with hearing loss in the coming years.
The next step for Teitz and her team is to conduct more preclinical studies in animals. They want to gather more data on the optimum dabrafenib dosage and schedule for cisplatin-induced hearing loss. They’re also trying to determine the best treatment plan for noise-induced hearing loss.
“Sometimes, you can predict when you're going to be in a noisy environment, but sometimes you can't,” Ingersoll says. “Even when you can't, our combined drug regimen with both dabrafenib and AZD5438 actually gave complete protection in mice when administered 24 hours after the noise exposure, which is a really big deal. There are currently no drugs out there on the market that can do this.”
Teitz says administering dabrafenib could offer hearing protection for people who are suddenly or unexpectedly exposed to high noise levels, including those who work in construction, landscaping, manufacturing, airports, and soldiers on the battlefield. The researchers were awarded a National Institutes of Health (NIH) grant to research how many hours or days after the noise exposure dabrafenib can be given and still be effective. Teitz hopes to collaborate with the military and then bring dabrafenib to the general public.
In addition to studying the effect of dabrafenib on hearing cells, Teitz and her team are also testing to see if the combination of dabrafenib and AZD5438 can also prevent kidney toxicity, another common side effect of cisplatin chemotherapy. It’s too soon to tell, but Teitz is hoping what works for the ear hair cells will also work for the kidney to create a win-win scenario.
Article originally appeared on Very Well Health
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