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St. Jude scientists discover the genetic basis of the side effects that sometimes accompany cancer treatment.

Two-year-old Skylar Ebanks loves to give and receive hugs and kisses. She reaches out to touch the faces of new people that she likes. But her short life has been a health rollercoaster.

When Skylar was just 5 weeks old, her parents noticed that her forehead was swollen and she was sleeping too much. Her family traveled from their home in the Cayman Islands to Florida for medical care.

Skylar had a brain tumor called ependymoma.

After an operation that partially removed the tumor, she traveled to St. Jude Children’s Research Hospital. There, Skylar had another operation and went through an experimental course of chemotherapy to treat her cancer. Although the experimental course can involve radiation treatment, her parents were allowed to opt out of radiation due to Skylar’s age.

However, shortly after starting chemotherapy, Skylar faced yet another challenge. Cisplatin, one of the drugs used to kill her cancer cells, had permanently damaged her hearing.


 

A St. Jude audiologist adjusts a hearing aid for tiny Skylar Ebanks. The chemo that helped save Skylar’s life also damaged her hearing.

 
 

Skylar’s mother, Mechon Ebanks, remembers the day she learned about her daughter’s hearing loss.

“I cried my eyes out,” she recalls. But she also knew that such setbacks can be part of the process of treating cancers effectively. Skylar’s doctors changed her treatments to an alternate therapy.

St. Jude doctors and researchers have been studying genes to better understand which patients might be most likely to develop side effects from particular chemotherapy drugs. The lessons they learn could change therapies for future patients.

Knowing the gene variations that leave children susceptible to treatment side effects will help doctors address problems a child might face. That information will enable researchers to develop safer therapies. It will also help physicians choose treatment combinations that maximize the ability to fight cancers while minimizing the risk of side effects. 

Delicate balance

Cancer therapies often include powerful drugs. Their ability to kill disease also means that they can cause unintended harm to other cells. Treatment remains a balancing act. If doctors administer too much of a therapy, it can cause damage, says Jun J. Yang, PhD, of St. Jude Pharmaceutical Sciences.

“But if you don’t give enough,” he says, “the tumor comes back.”

The ways that individuals respond to these drugs can vary widely. Researchers can trace some of those differences to the age of the patient or the dose of the drug. But even after scientists consider these factors, sometimes one patient tolerates a treatment regimen well, while another experiences a devastating side effect, Yang says.

William Evans, PharmD (at right), of St. Jude Pharmaceutical Sciences, and his colleagues (from left) Kristine Crews, PharmD and Barthelemy Diouf, PhD, PharmD, found that more than half of patients who inherited two copies of a certain version of the CEP72 gene developed nerve damage called peripheral neuropathy.

William Evans, PharmD (at right), of St. Jude Pharmaceutical Sciences, and his colleagues (from left) Kristine Crews, PharmD and Barthelemy Diouf, PhD, PharmD, found that more than half of patients who inherited two copies of a certain version of the CEP72 gene developed nerve damage called peripheral neuropathy.

Those findings suggest that differences in patients’ genes could be important. Now that the success rates for childhood cancer treatments have improved, doctors can turn some of their attention to improving quality of life after treatment.

“These kids are often very young, and we want them to have full, productive lives after cancer therapy,” Yang says.

Cisplatin remains an important drug for treating pediatric brain tumors like Skylar’s. However, hearing loss is one of the most worrisome side effects. Hearing loss occurs more often in the youngest children, which can significantly interfere with language development and learning. However, Yang notes there is variability both in who experiences this side effect and in the severity of the hearing loss.

To look for a genetic cause, Yang took a snapshot across all the genes of children in a St. Jude clinical trial whose brain tumors had been treated with cisplatin. He and his team looked for differences that occurred in the children with hearing loss. They found that changes in one particular gene, called ACYP2, popped up consistently in these children.

Right now scientists don’t know much about what this gene does and why it is linked to hearing loss from cisplatin therapy, Yang says. But research is underway at St. Jude to answer these questions.

Precision medicine

Meanwhile, other studies looking at genes linked to therapy side effects are moving closer to the clinic.

William Evans, PharmD, of St. Jude Pharmaceutical Sciences, and his colleagues recently looked at side effects from vincristine, a drug that physicians give up to 40 times during a child’s treatment for acute lymphoblastic leukemia (ALL).

These side effects occur in about one-quarter of children treated for ALL, and it most often shows up as nerve damage in the hands and feet. This condition is called peripheral neuropathy. Sometimes the damage leads to pain and tingling, and it can also interfere with coordinated movements like walking and eating with a fork and knife. The symptoms often, but not always, end after treatment, Evans says. But the pain can lead patients to delay or stop treatment before completion.

Now that St. Jude survival rates for ALL have reached 94 percent, researchers hope to lower the toxicity and improve quality of life while continuing to implement new treatments that advance cure rates closer to 100 percent.

Evans and his colleagues wanted to see if specific genes were linked to the pain and movement problems of this group of patients.

“If we found that, it may provide a way to identify the kids at greatest risk, and it also might give us some clues on how we might mitigate the toxicity,” he says.

Knowing the gene variations that leave children susceptible to treatment side effects will help doctors address problems a child might face. That information will help researchers develop safer therapies.

The scientists compared the genes from two groups of children: one group from a St. Jude clinical trial and the other group from another national clinical trial. They found that patients who inherited a certain form of the CEP72 gene had a higher risk and greater severity of vincristine neuropathy.

In laboratory tests, Evans and his team confirmed that cells with a specific version of this gene were more sensitive to vincristine. This drug works by interfering with the same steps in cell division that the CEP72 protein contributes to­—a process known as microtubule formation. Patients at highest risk of neuropathy inherited a form of the CEP72 gene that produces lower amounts of the CEP72 protein, making them more sensitive to vincristine.

“It makes biological and pharmacological sense that these changes would make cells more sensitive to vincristine,” Evans says.

Based on those results, Evans and his colleagues are planning a new clinical trial that will give children who carry this particular genetic signature doses of vincristine that are one-third lower. Their research indicates that this lower dose will be high enough to kill cancer cells but low enough to prevent nerve damage in the hands and feet.

Researchers (from left) Giles Robinson, MD, Oncology; and Jun J. Yang, PhD, and Clinton Stewart, PharmD, of Pharmaceutical Sciences; found that variations in a gene named ACYP2 were associated with as much as a four-fold greater risk of cisplatin-related hearing loss.

Researchers (from left) Giles Robinson, MD, Oncology; and Jun J. Yang, PhD, and Clinton Stewart, PharmD, of Pharmaceutical Sciences; found that variations in a gene named ACYP2 were associated with as much as a four-fold greater risk of cisplatin-related hearing loss.

Continued support and care

Although the ongoing research may not help Skylar regain her hearing, Mechon is grateful that what St. Jude researchers are learning could help future children with pediatric brain tumors. Since Skylar’s treatments, the little girl has been learning to live with her hearing loss. Her family has nicknamed her hearing aid “Roger,” and “he” helps her experience the sounds that surround her. Her hearing loss has slowed her learning and development, Mechon says. At home in the Cayman Islands, Skylar participates in music and speech therapy weekly as part of her ongoing recovery.

In addition, Skylar and Mechon will spend eight weeks at St. Jude this summer for an intensive therapy program tailored to Skylar’s developmental needs.

St. Jude isn’t just looking at cancer treatment,” Mechon says. “They’re also looking at post-treatment and paying attention to quality of life.” 

Reprinted from Promise, Summer 2015

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