In a classroom at St. Jude Children’s Research Hospital, five bright-eyed first-graders crowd around a table, paying rapt attention to their teacher. In response to a question, 7-year-old Allie Johnson confidently raises her hand.
During the next 45 minutes, Allie enthusiastically answers queries about days of the week, aces a fractions lesson and properly categorizes the term “rainbow” as a compound word. Tucking wispy hair behind her ear, she joins her classmates in reciting the rainbow’s hues: red, orange, yellow, green, blue, indigo and violet.
Then, using crayons and blunt-tipped scissors, the little girl with the iridescent smile carefully creates a rainbow of her own—a symbol of hope after a storm.
A new direction
Throughout the hospital, doctors and researchers are collaborating to find better ways to treat Ewing sarcoma, which has an overall survival rate of 75 to 80%. For children whose disease has spread or has returned after treatment, the outlook is grim: 15 to 20% survive.
“Over the past 20 years, there has been no significant improvement in outcomes,” says Michael Dyer, PhD, a Howard Hughes Medical Institute investigator and co-leader of the St. Jude Developmental Biology and Solid Tumor Program. “The idea of taking the chemotherapy that we already use for childhood cancer and mixing it up and intensifying doses just doesn’t work. We need new therapeutics.”
Several years ago, experimental drugs called PARP inhibitors were developed to treat breast cancer and ovarian cancers in adults. PARP inhibitors interfere with a process called DNA repair.
“These drugs were never on the radar for childhood solid tumors,” Dyer says.
But when scientists tested PARP inhibitors against different tumor types, Ewing sarcoma tumors were vulnerable to the compounds.
“Nobody expected that,” Dyer says. “It led to a firestorm of activity.”
Dyer and his colleagues subsequently discovered that Ewing sarcoma cells have problems repairing DNA damage. The St. Jude team quickly opted to exploit that weakness. They combined DNA-damaging chemotherapy with PARP inhibitors.
The results were dramatic. In the lab, the combo excelled at killing Ewing sarcoma tumors.
Using a special dosing schedule developed at St. Jude, not only did the combo have fewer side effects than traditional treatments, but it also killed Ewing cells more efficiently.
“This is truly a game-changer,” Dyer says, “building on the research that has been done at St. Jude in the past.”
Dyer and his colleagues moved quickly to share their findings with the world.
“We want other scientists to have access to our data,” Dyer says. “I think this kind of open communication is really important. All of the data is in an open database—every dose, every blood count, every image. It’s all freely available.”
St. Jude has rapidly moved the research from the lab to the clinic.
Based on the St. Jude findings, Dana-Farber/Harvard Cancer Center in Boston changed an existing Ewing clinical trial to incorporate a third drug. St. Jude is now a collaborator on that study, which is designed for teens and young adults.
A second clinical trial opened in the spring of 2015 at St. Jude. In that study, children with hard-to-treat or recurrent Ewing sarcoma will receive the PARP inhibitor talazoparib with a standard chemotherapy drug called irinotecan.
“It’s an exciting time for us,” observes Beth Stewart, MD, of St. Jude Oncology, who played an important role in the project. “About 11 months after our laboratory study was completed, the clinical trial opened. In the past, it could take from five to 10 years before discoveries in the lab made it to pediatric patients. Our super-comprehensive research shortened that length of time so that the right drugs are getting to the right patients much more quickly.
“At St. Jude, there’s a very nice relationship between those doing the research and those who are designing the clinical trials for patients,” Stewart continues. “There are very few places that do that as well as St. Jude does. It’s a true blessing for me to have the opportunity to work at such an institution—where we have such phenomenal resources and incredible collaborators right within the doors of our own hospital.”