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  • Posted: 10/12/2012

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TARGET: A focus on children’s cancers

By Richard Folkers

In an effort to decipher the genetics of cancer and prompt the development of better treatments, the National Cancer Institute and the National Human Genome Research Institute launched The Cancer Genome Atlas, or TCGA, an initiative now deeply invested in efforts to sequence, characterize, and catalogue the genomes of 20 different cancer types. But even though this research is conducted using tumor samples from thousands of people, some of its most impressive discoveries to date have been in cancers that don’t commonly affect the youngest cancer patients.

As any parent knows, children are not miniature adults—physically or emotionally. Nor are their bodies the same as ours biologically. That distinction becomes particularly acute when viewed through the lens of cancer. It only makes sense, then, to conduct a TCGA-like effort in children’s cancers.

Background map of the continental United States, with blue and yellow boxes pointing to the locations of 17 institutions that are collaborating on the TARGET initiative
The network of institutions collaborating with NCI in the TARGET initiative


Enter TARGET—Therapeutically Applicable Research to Generate Effective Treatments—NCI’s effort to use genomic technologies to search for therapeutic targets in cancers that affect infants, children, and adolescents.

TARGET is focused on five cancers that are common to, but not always exclusive among, children: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), neuroblastoma, osteosarcoma, and high-risk Wilms tumor. They were selected based on prevalence and on the availability of tumor samples—with a goal of 100 to 200 tumor samples per cancer—that have been collected and catalogued within TARGET’s strict scientific, technical, and ethical requirements.

The choices highlight the reasons for TARGET’s very existence. Neuroblastoma, a cancer that springs from immature nerve cells, affects mostly infants and children. Osteosarcoma, a form of bone cancer, principally afflicts children and adolescents. Wilms tumor, which begins in the kidney and can spread to the liver, lung, and lymph nodes, usually occurs in children under age 5.  ALL and AML together represent nearly one-third of cancers in children under age 15.

Even when children and adults face the same type of cancer, the hurdles they face can be very different. In adults, many cancers take years to develop, through accumulating genetic mutations, sometimes springing from environmental exposures such as tobacco smoke. Pediatric cancers usually involve fewer mutations and appear to be less likely due to environmental exposure. Children and adults also differ in the drugs and dosages they can tolerate, their responses to treatment, and the likelihood of remission. Importantly, as well, pediatric cancer patients are less likely to have “comorbid” conditions—diabetes, heart disease, and lung disease, just to name three—that complicate treatment in adults. Conversely, children are more likely than adults to be affected by the long-term side effects of cancer treatment.

One of TARGET’s early success stories came from the ALL TARGET team, which includes researchers from the Children’s Oncology Group, St. Jude Children’s Research Hospital, the University of New Mexico, and the National Cancer Institute.  For 15 percent to 20 percent of children diagnosed with this most common of all pediatric cancers, standard chemotherapy doesn’t work, and the reasons why were unclear.  The TARGET research team analyzed the genes of 221 children with high-risk ALL. Their studies found mutations in a group of proteins called JAK, which can help cancer cells survive and grow.

“The National Cancer Institute… wasted no time bringing these findings to the clinic,” reported the journal Cancer Discovery in June 2012. “In September 2010, they began a phase I clinical trial testing a drug called ruxolitinib that inhibits JAK proteins... The ruxolitinib trial is one of the first tangible results from NCI's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative..."

In another recently published result, from August 2012, the ALL TARGET team reported the identification of genetic alterations that underlie a subtype of ALL known as Philadelphia chromosome-like ALL. The study delineated newly discovered alterations in genes that regulate how cells grow and proliferate, and it showed that some patients might benefit from existing targeted therapies that zero in on the ALL-altered genes.

“This work is another example of how a detailed analysis of the genetic changes present in cancer cells can identify the changes that are critical for cancer cells to escape normal growth controls and allow them to resist standard chemotherapy treatments, but also serve as an Achilles’ heel that can be attacked by drugs targeted at these genetic changes…” said Stephen Hunger, M.D., a professor of pediatrics at the University of Colorado and chair of the Children’s Oncology Group ALL Committee.

Progress against cancer involves lengthy, intricate research. Scientists who develop new cancer therapies owe a great debt to patients who participate in clinical trials that test the latest interventions. In that area, another significant gulf between children and adults becomes apparent. It has been estimated that fewer than 3 percent of adult cancer patients in the United States participate in clinical trials. In children under age 15, half or more participate.  This high participation rate has allowed TARGET research teams to successfully study childhood cancers that occur much less commonly than most cancers arising in adults.

“The TARGET initiative represents the best of team science, with clinical and laboratory researchers working together to identify the recurring genomic changes in five major childhood and adolescent cancers,” said Malcolm Smith, M.D., National Cancer Institute.  “The knowledge gained through TARGET will provide the scientific framework for future advances in identifying more effective treatments and curing more children and adolescents diagnosed with these cancers."