Grand Rapids — Researchers here at Helen DeVos Children's Hospital are using genetic data mined from tumor cells to develop personalized treatments for pediatric cancer patients.
The nation's first clinical trials of personalized treatment for children's cancers are underway at 15 hospitals across the country and one international hospital in Lebanon under the leadership of Dr. Giselle Sholler, a pediatric oncologist and endowed director of the Haworth Family Pediatric Oncology Innovative Therapeutics Clinic at DeVos, which is part of West Michigan-based Spectrum Health.
Participating hospitals belong to the Neuroblastoma and Medulloblastoma Translational Research Consortium, which is dedicated to advancing personalized treatment of two of the deadliest and most aggressive childhood cancers. Neuroblastoma is a malignant tumor, usually in the adrenal gland; medulloblastomas are fast-growing brain tumors.
Called "precision medicine," the use of genetic profiling to identify and treat the specific DNA mutations that cause cancer is the brave new world of cancer research. Patients have come to DeVos from across the globe to participate in the trials. Clinical trials of precision medicine are also underway at C.S. Mott Children's Hospital in Ann Arbor and Detroit's Barbara Ann Karmanos Cancer Institute.
In January, the White House launched a Precision Medicine Initiative, dedicating $215 million in President Barack Obama's 2016 budget request to study how an individual's genetic makeup can be used to shape a personalized plan for disease prevention, diagnosis and treatment.
On a recent day, children from California, England and Israel were among the boisterous gaggle in the clinic's playroom.
Children accepted for the trials have cancers previously deemed incurable. The survival rate for children with recurrent neuroblastoma is less than 10 percent.
Twelve-year-old Laura VanDerBos of Grand Ledge has had more treatment options from which to choose since joining the trials in December, including medications that have fewer side effects than previous treatments.
"We've been working with Dr. Sholler to find the right balance of treatment and quality of life — just enough medicine to keep her disease at bay, and not so much that she can't get out and enjoy life," said Trisha Cwayna, Laura's mom.
Laura was 3 years old when she was diagnosed with neuroblastoma. She is now experiencing her fourth relapse of the disease. In her short life, Laura has had more than 20 rounds of chemotherapy and spent months at a time on IV nutrition. She's had a stem cell transplant, multiple surgeries, radiation treatment and more than 100 blood transfusions.
"We're very involved in the treatment decisions," Cwayna said, when asked how the trial differs from prior treatments. "Dr. Sholler will get a piece of tumor and analyze it, and then say 'These are some of the medications that work on her tumor,' and then we decide.
"Dr. Sholler has the medical expertise, I have the Laura expertise, and we work together."
One chance for treatment
Such personalized cancer treatment is now within the realm of research, and only available through participation in clinical trials.
Anticipating it will eventually become mainstream, Spectrum-owned Priority Health, the state's second largest health insurer, recently became the first health insurance company in the United States to adopt standard coverage of genomic profiling, at a cost of about $6,000 or more per patient, for the toughest pediatric and adult cancers.
"There are some patients whose cancers are so aggressive or late stage that they may only get one (chance for) treatment with one drug," said Dr. John Fox, associate vice president of medical affairs at Priority Health. "The question is, is there a drug that's going to be more effective?
"We're paying for it in selective circumstances where there's a high unmet need. For those very rare or aggressive cancers, we're paying for it because we may not have a lot of time."
Tiny Kian Musgrove, who turns 3 next month, was 1 year old when he started to lose his balance. At first, doctors in the English city of Newcastle upon Tyne thought it was just a virus. By the time he was diagnosed with neuroblastoma three months later, Katherine Musgrove worried her son would not survive the surgery to remove his tumors.
"Kian had tumors all through his bones and his bone marrow, and the main one where it started was in the adrenal gland. He had it in the lymph nodes, too," said Musgrove, who raised 100,000 pounds or about $150,000 on the Internet and through special events to bring Kian to Grand Rapids for treatment. "He had 27 tumors all over his body."
After high-dose chemotherapy, immunotherapy, radiation therapy and stem cell treatment, Kian is in remission. Through a clinical trial at DeVos, he will take an oral medication, called DFMO, for two years in hope of preventing a relapse by targeting an enzyme associated with the disease.
"Neuroblastoma has a really, really high risk of relapse. There's not very many children that it doesn't come back, even if they're in the clear," Musgrove said. "At first I thought the only option was wait until he relapses and then fight the relapse.
"I wanted the treatment because the treatment is supposed to prevent relapse. It's not a guarantee, which I know, but I think I want to try it, and everything's worth a try."
'A cell that went wrong'
On a recent morning at the clinic, a tiny 2-year-old girl underwent surgery to remove a large tumor from her liver. A small portion was placed on dry ice and whisked away to Sholler's laboratory.
"We will grow that patient's tumor cells in culture so we can test different drugs and do the genomic profiling," Sholler said.
A portion of the cancer tissue was sent to the hospitals' partner in the clinical trials, Phoenix, Arizona-based Translational Genomics Research Institutewhich does the genomic profiling for the trials.
Scientists there use powerful technology to sequence the complete set of DNA and RNA that make up a child's genome, or genetic profile. DNA molecules are made up of pairs of twisted strands that contain chemicals labeled A, T, G and C. If scientists figure out the exact sequence of those letters, they can identify changes in the sequence, called mutations, that can cause cancer.
Profiling an individual's genome generates more than 200 billion bits of information per patient and can takes weeks or months to complete. For these clinical trials, Dell Inc. has donated money as well as its computing cloud, a huge network of computers to store and process information. Dell's cloud dramatically increases the speed of TGen's computation and analysis so the consortium's doctors and scientists get real-time information to fight the aggressive cancers.
Asked why some children get cancer while others don't, Sholler said it's typically random. Unlike cancers in adults, which often are caused by environmental factors such as smoking or sun exposure, children's cancers are mostly accidents of nature. They often occur during a growth spurt, when cells are rapidly dividing.
"Cancer essentially is a cell that went wrong," Sholler said, noting that every cancer begins with a DNA mutation. "In division of the cell, mutations happen all the time. We all have mutations, but normally when the DNA mutation happens, the cell just dies.
"When the DNA mutation happens in a cell that doesn't know how to stop dividing, that's when a cancer forms. The cell just keeps dividing ... and it's lost the ability to undergo cell death. We have to find a way to target those cells and see what it was in the DNA mutation that made the tumor do this, so we can we shut it off."
First trial's results published
This is Sholler's third one-year trial to test the effectiveness of personalized treatment for pediatric cancer patients. The trials last only a year, she noted, because medical technology is advancing so rapidly.
The results of her first trial, which involved 14 patients with neuroblastoma, were published in the March issue of the journal Cancer Medicine. All participating patients had relapsed cancer or cancer that had not responded to previous treatments.
The neuroblastoma was stabilized or reduced in 64 percent of the children, with no adverse effects from the targeted medication. On average, it took 5.9 days from the time of biopsy to complete the genomic profiling, and 12.4 days from biopsy to the start of treatment targeting the rogue DNA determined to have caused the cancer.
"We just want her to have joy — we want her to find treatment that allows her to participate more fully in life," Cwayna said of her goal for Laura, who turned 12 on Friday.
"With her birthday this week, we didn't want her to be feeling terrible from chemo, so we worked with Dr. Sholler to be able to change things up a bit and give her a break. She really, truly is a pioneer."