Inhibiting Toll-like receptor 4 stopped it from accumulating cisplatin, thereby halting the hearing damage caused by the cancer treatment.
Researchers are trying to get a better understanding of how the chemotherapy drug cisplatin works in childhood cancer survivors, with the goal of eliminating the toxic adverse effect (AE) of hearing loss.
A team at the University of Alberta has identified a receptor in cells that could help accomplish this, if it were inhibited in pediatric patients receiving cisplatin. Cisplatin is a frequently used and effective chemotherapy indicated to treat solid tumors in children. The drug contributes to an 80% survival rate over 5 years, according to researcher Amit Bhavsar, PhD.
The difficulty with cisplatin treatment has been its significant AEs. Nearly 100% of patients who receive higher doses of the drug show some degree of permanent hearing loss, and the ability to prevent this effect would dramatically improve the quality of life of cancer survivors after they recover.
According to the study, many investigators have tried to eliminate this AE by looking at it genetically, trying to determine the underlying risk factors for hearing loss. Some research has been done to determine the progression of hearing loss as an AE, but the study authors said the instigating factor of the hearing loss has remained unknown. To address this issue, Bhavsar and his team looked at the chemical composition of cisplatin itself and were able to identify a specific receptor that it turned on.
This receptor is the Toll-like receptor 4 (TLR4), which is involved in the body’s immune response. TLR4 crosses the cell membrane, leaving a portion of itself outside the cell to look for various signals that indicate damage or danger.
“It’s a receptor that your body normally uses to detect when there’s some sort of issue, like an infection,” Bhavsar said in the press release. “This receptor will turn on, and it’ll start producing these signals that tell the cell it’s under stress. Unfortunately, in the case of cisplatin, those signals ultimately lead to the death of the cells responsible for hearing.”
The cells impacted by TLR4’s signals are located in the cochlea of the ear, where they work by translating vibrations into electrical impulses. Cisplatin also accumulates in the kidneys, but there it can be flushed out and diluted. The researchers noted that in closed systems such as the ear, the drug accumulates and damages the cells.
“These cells don’t renew,” Bhavsar said in the press release. “You really only get one shot and if they’re gone, you’re in trouble. The hearing loss is permanent.”
According to the investigators, the only way to prevent the damage is to stop the signals TLR4 produces that lead to the accumulation of cisplatin. To confirm this theory, the researchers used zebrafish models to examine neuromasts, which are sensory cells that behave similarly to the human hair cells typically damaged by cisplatin. Bhavsar said that they proved that inhibiting TLR4 led to an inhibition of the damage on the sensory cells.
“It really does open the door for potential therapeutics,” he concluded.
Researchers pinpoint possible way to prevent permanent hearing loss caused by common childhood cancer drug [news release]. University of Alberta; May 13, 2021. https://www.ualberta.ca/folio/2021/05/researchers-pinpoint-possible-way-to-prevent-permanent-hearing-loss-caused-by-common-childhood-cancer-drug.html. Accessed May 20, 2021.