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Some of the most successful cancer-fighting drugs also cause hearing loss in children. In addition to saving lives, St. Jude is actively seeking ways to reduce such side effects.
Five-year-old Alex Moore waits intently inside a soundproofed booth in the Rehabilitation Services department at St. Jude Children’s Research Hospital. As a faint, fleeting “beep” sounds in his left ear, he hurls a toy block in the direction of St. Jude audiologist Johnnie Bass, who monitors an audiometer outside of the booth.
Ricky and Lindsay Moore watch as their son undergoes conditioned play audiometry, a modified version of the standard hearing test used for younger patients. When Alex hears a beep, he throws a block. The process is repeated at gradually higher frequencies.
When he was 3 months old, Alex began undergoing treatment for the eye cancer retinoblastoma. As a result of his exposure to the chemotherapy drug carboplatin, Alex suffered ototoxicity, or hearing loss.
“Learning Alex had suffered hearing loss was almost as surprising to me as his initial diagnosis,” Lindsay says. “Although we knew it was a possibility, it was not common.” Alex has moderate-to-severe, high frequency hearing loss in both ears.
“He’s wearing hearing aids in both ears, and he has adjusted well,” Ricky adds.
Scientists at St. Jude are interested in learning what causes such problems. An answer could one day help clinicians offset the hearing loss that occurs in children as a result of treatment with cancer-fighting drugs such as carboplatin and cisplatin.
As sound waves race into the inner ear at hundreds of miles per hour, their energy generates waves in the fluid-filled part of the inner ear. Within that fluid are rod-shaped cells covered with hair-like cilia. The energy from sound waves causes the hair cell cilia to swing back and forth quickly in a steady rhythm. When the sensory hair cells are damaged in non-mammals, such as fish, chicken and birds, the cells can be regenerated. But when hair cells are damaged in humans, the opposite is true. That causes permanent problems for children whose hearing is damaged during cancer treatment.
Jian Zuo, PhD, of St. Jude Developmental Neurobiology, and his team of researchers are comparing the regeneration of hair cells in non-mammals with what happens in the mammalian ear. “When a non-mammal’s sensory, mechanical neurons are destroyed because of ototoxic damage, they are able to regenerate hair cells,” Zuo says. “We are trying to determine how you can make a mammal regenerate hair cells after damage.”
Researchers are trying to determine how the delicate cell system in the ear actually hears sound. Humans and other mammals can detect extremely small vibrations of sound, with a minimum range of one nanometer in amplitude. Most humans do not consciously detect such a faint sound, but the hair cells inside the ear respond with movement.
“It’s quite remarkable that all mammals can distinguish low-frequency and high-frequency sounds,” Zuo says. “The sound can range in magnitude from very low-zero decibels, like a whisper on a quiet, summer night—to 120 decibels—that’s as loud as an airplane taking off.”
In mammals, the rod-shaped body of the hair cell contracts and then vibrates in response to sound waves, amplifying the sound. While both mammals and non-mammals have cilia on their hair cells, only mammals’ hair cells have prestin, a protein motor that drives this cellular contraction.
According to Zuo, when hearing loss occurs, damage is done to the mechanical, sensory neurons in the cochlea, the small organ in the inner ear.
Because of toxicity issues with the chemotherapy drug cisplatin, physicians sometimes use carboplatin as an alternative. But carboplatin may also cause hearing problems.
“Some laboratory studies have shown that carboplatin has caused damage to the outer hair cells of the cochlea, while other studies have shown damage to inner hair cells only and no damage to the outer hair cells,” Bass says.
Outer hair cells receive neural input from the brain, while inner hair cells send neural signals to the brain.
For the past two years, St. Jude has partnered with the University of Memphis in a study concerning sounds produced by healthy ears in response to acoustic stimulation. The protocol enrolls children with the eye cancer retinoblastoma who are receiving carboplatin.
The procedure involves putting a probe with a soft tip into the child’s ear. A sound stimulates the ear, and the probe measures return vibrations from the hair cells. A decrease in these levels often indicates permanent damage to those cells. St. Jude staff will compare measurements of outer hair cell function and inner hair cell function in patients receiving carboplatin. Clinicians will use that information to determine if changes in cochlear function occur and if damage is occurring to one or both hair cells.
“This will help us come up with better intervention, management and treatment of these patients if they do experience hearing loss because we’ll know better about where the damage is occurring,” Bass says.
To obtain a better understanding of how the entire hearing process works, Zuo’s team is manipulating particular proteins in cells to explain how a specific gene or cell contributes to the process. When investigators inactivated the protein prestin, Zuo found that the entire hearing process was disrupted.
Recent work by Zuo’s team involves the manipulation of genes in the hair cells. Results on the retinoblastoma gene have indicated that when the hair cells reenter the cell cycle, they cannot complete it and they die. Zuo and his colleagues are now targeting surrounding cells with the aim of regenerating new cells.
“We hope that further genetic manipulation of genes in those cells would give those cells the ability to reenter the cell cycle and start to proliferate, then try to differentiate into new hair cells—just like they do in birds and fish,” Zuo explains.
Bass says the main goal of the study is to detect hearing loss as early as possible. “Our question was, ‘Can we catch damage before it even shows up as hearing loss?’” Bass says.
While stopping chemotherapy might not be an option, counseling the family about the child’s risk for developing future hearing loss could be helpful. Clinicians will warn Alex Moore’s parents about the dangers of exposure to loud noises or taking other medications that might cause further hearing deficit.
“We’re using all the information that we’re gathering to understand where hearing loss is occurring, how early it is occurring and how we can catch it early,” Bass says. “The outcome of that is being able to counsel patients better and communicate with physicians our concerns with hearing, especially in visually impaired patients.”
Reprinted from Promise Spring 2008
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