St. Jude patient Allie Johnson

Ewing Sarcoma: Changing Hues

A spectrum of discoveries in St. Jude labs and clinics offer promise for patients with Ewing sarcoma.

St. Jude Ewing sarcoma patient Allie Johnson delights in creating rainbows, such as this painting.

St. Jude Ewing sarcoma patient Allie Johnson delights in creating rainbows, such as this painting. 

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.

The glowering sky

For Allie, the clouds began to gather in 2014, after a playground tumble.

“I fell off the really tall monkey bars at school,” Allie explains. “My back kept hurting, and they found out I had a tumor. At a hospital in Oregon, they took out some of my tumor. Then I came to St. Jude.”

The pain that Allie and her parents originally attributed to a fall was actually a tumor wrapped around her lower spine. Allie had a type of bone cancer called Ewing sarcoma, which had also spread to her lung. Instead of pursuing standard treatment in Oregon, her parents, Richard Johnson and Kelli Gambucci, opted to enroll Allie in a clinical trial at St. Jude.

“From my research about St. Jude and everything they’re doing for children, it was a no-brainer,” says Allie’s dad, Rich Johnson. “We quickly realized we’d made the right choice. I have nothing but wonderful things to say about St. Jude and the progress that they’ve made and the loving care that my daughter and my family get while they’re there.”

 Thus far, Allie has responded well to treatment, which has involved chemotherapy.

“She’s a great example of how remarkable the response can be to therapy,” says her St. Jude oncologist, Tamara Chang, MD. “She has very minimal disease left right now, and we’re only 18 weeks into therapy, which is awesome.”

After undergoing surgery to remove the remaining tumor, Allie will receive radiation therapy.

“She’s spunky and bright and adorable,” Chang says. “She’s always cheerful, even when she’s not feeling well. She’s a rock star.”

 

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.” 

Sifting the spectrum of mutations

Meanwhile, across campus, computational biologist Jinghui Zhang, PhD, helped lead an international collaboration to explore the genetic landscape of Ewing sarcoma. The results were astounding. Scientists not only pinpointed frequent mutations that occur together in this cancer, but they also identified a subtype of Ewing that is linked to a poor prognosis.

The research provides the most comprehensive picture to date of the genetic changes that help Ewing sarcoma grow and, in many cases, recur. The work took place as part of the St. Jude – Washington University Pediatric Cancer Genome Project, in conjunction with the Institut Curie-INSERM through the International Cancer Genome Consortium.

Jinghui Zhang, OhD

Computational biologist Jinghui Zhang, PhD, recently helped lead an international collaboration to explore the genetic landscape of Ewing sarcoma.

“This is an important step toward developing more effective diagnosis and treatment,” Zhang says.

Zhang and her colleagues already knew that mutations in STAG2 and TP53 genes played a role in some cases of Ewing sarcoma. But the recent study proved that children who have both of those mutations also have a lower chance of surviving their disease.

Fortunately, the PARP inhibitor combo appears to be effective against this subtype. In the lab, the combination therapy was effective against 70% of Ewing sarcoma tumors that featured the STAG2 and TP53 mutations.

 

True colors

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.

Another St. Jude team quickly moved their Ewing discoveries from the lab to the clinic, including Anang Shelat, PhD, Michael Dyer, PhD, and Beth Stewart, MD

Another St. Jude team quickly moved their Ewing discoveries from the lab to the clinic. Those researchers included (from left) Anang Shelat, PhD, Michael Dyer, PhD, and Beth Stewart, MD.

“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.”

Pot of Gold

While teams of doctors and researchers explore the mysteries of Ewing sarcoma and work to develop better treatments, Allie Johnson pursues her own activities, which are just as important to her.

 Those pastimes include preparing the perfect cup of pretend tea for an unlikely group of friends.

 “My brother is not invited to my tea parties,” says Allie, with a mischievous smile. “Only my animals and my mom are invited. The ones who come to my tea parties are Purple Monkey and Shadow the dog, and three fake people. They’re my dolls. Their names are Josey, Medium Josey and Small Josey.”

 When she’s not hosting tea parties, undergoing treatment or attending school—she’s a voracious reader—Allie spends her time building extravagant Lego creations, carefully applying makeup to her mom’s face, and dreaming of the day when she can return home to Oregon. There, she will enjoy a party with her school friends, ride her bicycle, eat strawberries from the garden and get a kitten. Those simple activities are, for Allie, rewards at the rainbow’s end.

Reprinted from Promise, Summer 2015

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