TARGETing pediatric blood cancer: Changing treatment for kids

A new molecular map of pediatric acute myeloid leukemia (AML) illuminates previously unknown causes of the disease and may lead to more effective treatment strategies developed specifically for children.

Conducted by an international team of scientists and pediatric oncologists, the study found that kids with AML have significantly different cancer-driving mutations than those seen in adult AML patients, with far more diversity observed in children. The few mutations that are common to all age groups appear to interact differently in younger versus older patients, a new finding with profound clinical implications.

Their results reinforce the need for, and may result in, a better way of classifying pediatric patients, based on specific genetic and epigenetic changes that sustain their disease. This informs treatment decisions and clinical trial participation, a major consideration for this rare but deadly cancer.

Dr. Timothy Triche, Jr.

“Pediatric cancers arise from fundamentally distinct processes compared to adult cancers, and it is important to recognize this if we are to have a tangible impact on these children’s lives,” said Timothy J. Triche, Jr., Ph.D., an assistant professor at Van Andel Research Institute and co-first author of the study, which was published today in Nature Medicine. “This study provides scientists and physicians with a strong foundation on which to build effective, patient-centered treatment strategies that are desperately needed for children with AML.”

The findings are the result of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) study, a collaborative project spearheaded by the Children’s Oncology Group (COG), whose member institutions care for more than 90 percent of children diagnosed with cancer in the U.S., and the National Cancer Institute (NCI) at the National Institutes of Health. It was led by Soheil Meshinchi, M.D., Ph.D., a faculty member and pediatric AML researcher at Fred Hutchinson Cancer Research Center and professor and attending physician at Seattle Children’s Hospital/University of Washington.

The project, nearly a decade in the making, included scientists and physicians from more than a dozen groups and institutions, both in the U.S. and abroad. The findings represent the most comprehensive characterization of pediatric AML to date.

All cancers result from damage to a person’s DNA, but the type and location of damage that gives rise to pediatric, adolescent and adult cancers vary widely. Because most cancer drugs are developed to treat adult patients, these differences can have drastic ramifications on treatment response in pediatric cases.

Click to enlarge.

For example, unlike its adult counterpart, the team found that pediatric AML is more frequently characterized by genetic fusions, an aberrant mash-up of two genes. Many of gene fusions in children are not targeted by any available drug treatments. Conversely, a number of the most common cancer-driving gene mutations found in adult AML are rare or absent in pediatric cases.

“It’s not just mutations, but also their interaction with other genetic and metabolic variations that impact the disease’s susceptibility to one treatment over another,” Triche said. “There are kids who respond well to standard regimens, and there are kids who don’t. The latter currently have few options. We now have a better idea of why that is, and we hope that our findings spur a change in how patient risk is classified.”

Because the pediatric AML patient pool is so small, large-scale, comprehensive studies are difficult to undertake, which makes today’s report that much more remarkable, Triche says. In all, samples from 1,023 children enrolled in COG-affiliated clinical trials were included in the dataset.

The team included scientists and clinicians at Fred Hutch; NCI; COG; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Science; Jane Anne Nohl Division of Hematology, University of Southern California Norris Comprehensive Cancer Center; USC’s Keck School of Medicine; Michael Smith Genome Sciences Centre, British Columbia Cancer Agency; St. Jude Children’s Research Hospital; Eramus MC-Sophia Children’s Hospital; Brigham Young University; University of Utah; Nemours Center for Cancer and Blood Disorders, Alfred I. DuPoint Hospital for Children; and Children’s Mercy Hospitals and Clinics.

Additional Information:

TARGET is supported by NCI award U10CA98543; work also was supported by NCI contract HHSN261200800001E. Computation was supported in part by Fred Hutchinson Scientific Computing, University of Southern California’s Center for High-Performance Computing and NSF Award ACI-1341935. Additional support came from COG Chairs U10CA180886 and U10CA98534; COG Statistics and Data Center U10CA098413 and U10CA180899; COG Specimen Banking U24CA114766; R01CA114563 (Dr. Meshinchi); St. Baldrick’s Foundation (Dr. Jason E. Farrar, Dr. Timothy J. Triche, Jr., Dr. Soheil Meshinchi); Alex’s Lemonade Stand (Dr. Soheil Meshinchi), Target Pediatric AML (TpAML); P20GM12193 (Dr. Jason E. Farrar); Arkansas Biosciences Institute (Dr. Jason E. Farrar) and the Jane Anne Nohl Hematology Research Fund (Dr. Timothy J. Triche, Jr.).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.