St. Jude researchers find clues to preventing hearing loss and other side effects of chemotherapy.
A free concert is underway in the waiting area of the Solid Tumor Clinic at St. Jude Children’s Research Hospital. The music being played with great force on a tinny-sounding toy piano consists of only four notes. But to anyone who knows the performer, 13-month-old DJ Todd, it sounds beautiful.
That’s because DJ is lucky to be able to hear the high notes. “When you see him playing, it looks like he hears and responds to everything,” says DJ’s father, Darrick Todd. “But the computer says he has hearing loss.”
Diagnosed with aggressive neuroblastoma at 2 months old, DJ has spent most of his young life as a St. Jude patient, undergoing intensive treatments to destroy this cancer of the nerve tissues. Thanks to the treatments, which included chemotherapy with a drug called cisplatin, DJ’s cancer has now virtually disappeared.
However, although cisplatin is a powerful weapon against neuroblastoma and other cancers, it can also penetrate and kill healthy cells—in the inner ear, for example, as well as in nerves and kidneys.
Like DJ, most children treated with cisplatin experience some degree of hearing loss, particularly in the upper ranges. In some cases, the loss is irreversible. Nerve and kidney damage are other major side effects.
Still, cisplatin is likely here to stay—at least for now, says Alex Sparreboom, PhD, of St. Jude Pharmaceutical Sciences.
“Despite efforts throughout the world to come up with newer drugs, it’s unlikely that we’ll ever see the time when we won’t use cisplatin anymore, because it is part of a curative treatment regimen,” he says.
“It may seem like achieving a cure is worth the trade-off of having these side effects, but the impact on quality of life is astonishing,” he adds. “So it’s important to try to do something about the problems this drug causes.”
Discovery of a major key
The big challenge is finding ways to block the side effects of cisplatin without weakening its power to fight cancer. Attempts by researchers during the last decade have yielded disappointing results, both for cisplatin and related drugs in the platinum family.
But a hopeful note was struck recently, thanks to Sparreboom and other scientists. Their research has identified a key to the side effects caused by platinum drugs.
This key is a protein called OCT2.
OCT2, the research shows, transports cisplatin into vulnerable healthy cells. And cisplatin is not OCT2’s only dangerous passenger. Recently, Sparreboom and his St. Jude colleagues discovered that oxaliplatin, a different platinum drug, relies on OCT2 to gain entry into nerve cells.
“Oxaliplatin, which is used to treat colorectal cancer, causes pretty harsh nervous system toxicity in patients,” says postdoctoral fellow Jason Sprowl, PhD, who led the project with Sparreboom. “We were wondering why, and if there is a way to decrease the chances of it happening.”
Building on their finding that OCT2 was involved, the scientists decided to ask a simple question in the lab: Would drugs that target OCT2 ease side effects by keeping oxaliplatin out of cells?
Sprowl and Sparreboom tested an FDA-approved drug, cimetidine, and the results were definitive: a single dose protected nerves from damage by oxaliplatin.
Variations on a theme
So, will a similar strategy one day protect children from cisplatin-related side effects?
The answer is likely yes, Sparreboom says, based on their findings and a growing body of research. “The interesting thing with cisplatin is that all three side effects—the hearing loss, the kidney damage and the nerve damage—are connected to this same transporter, OCT2,” he says.
Therefore, blocking OCT2 may prove to be the winning strategy to protect against many side effects at once.
“It looks interesting, very promising,” Sparreboom says.
His team is now conducting initial studies in patients, which are showing that cimetidine does not hamper the cancer-fighting ability of cisplatin. The researchers are also exploring the potential value of other drugs that block OCT2.
“The best outcome imaginable would be that we could get rid of specific cisplatin-related toxicities in the future,” Sparreboom says.
This would be wonderful news for future patients like DJ, who may one day be spared the risk of lifelong challenges that may occur because of platinum drug treatments.
Coda: Next steps for DJ
DJ will likely be fitted with hearing aids soon, to help him catch the high-pitched sounds that are necessary for normal speech development.
“They’re saying that he needs it for speech, so he won’t miss any of the developmental stages he’s coming up to,” Darrick says. “We’re just trying to cope with it right now, trying to deal with the fact that he’s going to have to have two hearing aids.”
“He’s been through so much,” adds Sandy Crenshaw, DJ’s mother. But through it all, DJ has remained happy and active. “He has been a strong little baby,” she says, smiling. “It shocks a lot of people.”
DJ may be able to hear his parents’ discussion, but he isn’t listening. He’s too busy being a typical 1-year-old. As the volume of the music from his piano peaks, he accompanies it with a crow of delight. And as abruptly as the concert started, it’s over.
Time for the next big adventure.
Abridged from Promise, Winter 2014