First Genomic-based Pediatric Trials Launched in Neuroblastoma

Last November, Dell announced it was donating an initial $4 million including cloud-computing technology to speed up development of personalized medicine trials for children with neuroblastoma and other pediatric cancers. According to the American Cancer Society, about 650 children under the age of 15 are diagnosed with neuroblastoma each year. It is the second most common tumor in children and the most common cancer in babies less than 1 year old. Although 5-year survival rates for children with low- and intermediate-risk neuroblastoma is higher than 95%, only between 40% and 50% of children with high-risk neuroblastoma survive long-term. The disease is responsible for one in seven pediatric cancer deaths.

To increase survival rates, researchers need the ability to analyze a patient’s genomic profile quickly and then determine highly targeted, effective therapies for that patient’s tumor type, said Giselle Sholler, MD, Chair of the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC); Co-director of the Van Andel Research Institute (VARI) Pediatric Cancer Translational Research Program; and Director of the Haworth Family Pediatric Oncology Innovative Therapeutics Clinic at the Helen DeVos Children’s Hospital in Grand Rapids, Michigan.

Pilot Study

To accomplish that goal, last spring, Dr. Sholler launched the first genomic-based personalized medicine pediatric cancer trial in neuroblastoma. “The program developed over the past 5 years while we were profiling all of our neuroblastoma patients by isolating the neruoblastoma cells from their bone marrow and noticing that they had very different tumor profiles,” says Dr. Sholler.

Dr. Sholler worked with Craig Webb, PhD, Co-director of VARI’s Pediatric Cancer Translational Research Program, who developed the computer algorithms to analyze the RNA expression of the tumors of each of the five patients in a pilot study, completed in 2010, and then found drugs that targeted each tumor type. All of the children had relapsed from front-line therapy and had no other therapeutic options.

“The Institutional Review Board wanted us to be able to get the data back in real time because neuroblastoma tumors grow so quickly. Our goal was to be able to do a biopsy of each patient’s tumor, analyze the data from the gene-expression profile, generate a report, and then bring together members of our molecular tumor board, which includes researchers, oncologists, pharmacists, bioinformaticians, pathologists, and radiologists. The board would discuss each patient’s clinical care so far, the status of the patient, and, based on the report, the list of drugs that target the patient’s tumor, so that we could create an individual treatment plan. All of this would be done in less than 2 weeks,” said Dr. Sholler.

Larger Trial

A larger 14-patient trial opened last summer at five centers by the NMTRC in collaboration with Intervention Insights—there are 11 clinical trial sites nationwide and 7 more are expected to open this year—and three neuroblastoma patients have enrolled so far. Implementation of Dell’s cloud supercomputer, which is 1,200% faster than the current technology in use at the Translational Genomics Research Institute (TGen), where the data is stored, will allow Dr. Sholler to not only sequence each patient’s RNA expression profile, but his DNA expression profile as well, in less time.

“Sequencing itself takes about 2 weeks, but the analysis that takes time too. Right now, 2 months is the quickest we can get good data to make clinical decisions. The supercomputer will shorten that time to about 2 weeks for RNA sequencing and 1 month for DNA sequencing. We will make clinical decisions based on the RNA sequencing and expression and go through a cycle or two of therapy and then have our second molecular tumor board meeting, when we will have the DNA information as well and we can reassess treatment options,” said Dr. Sholler.

Future of Personalized Medicine

“We choose to fund the personalized medicine trials of the NMTRC because neuroblastoma is such a deadly cancer and we wanted to take the cancer and use it as the first model for how we will do this kind of pediatric research going forward,” said James M. Coffin, PhD, Vice President and General Manager of Dell Healthcare and Life Sciences. “This model of personalized medicine is transferable to every kind of cancer, and we expect to build one of the largest supercomputing platforms in the genomic field.”

Analysis of the genomic profiling will be done using software developed by VARI’s Pediatric Cancer Translational Research Program and TGen, which Dr. Sholler can then use to create a treatment plan for each patient, using FDA-approved drugs with known pediatric dosing for the specific tumor type. For this study, the FDA has approved the use of a combination of up to four drugs from any drug classification.

“Our goal is to offer these children a good quality of life, and we are not leaning toward the use of high-dose chemotherapies. Instead, we’re looking at lower-dose targeted therapies in combination with maybe one or two chemotherapies,” said Dr. Sholler.

Although Dr. Sholler’s trials are the first attempt in personalized medicine for children with relapsed disease, if successful, genomic-based medicine for pediatric patients with cancer may eventually be used in the front-line setting, where the greatest chance for cure may be possible.

Improving Cure Rates

“Once a child with neuroblastoma has relapsed, there is no curative therapy. We have been able with lower-dose therapies to extend the lives of these children over the past 5 years. If we can understand what’s driving the tumors, stop them from growing, and ultimately kill them, that’s a cure,” Dr. Sholler said.

“I’m hoping that as we validate this type of methodology and bring this to upfront therapy, that’s when we’re going to see the cure rates change. Right now we treat all the kids with the same high-dose therapy, but only 50% are responding. We’re not serving the other 50% very well,” she concluded. ■