TARGET Initiative Leading the Way to New and Exciting Discoveries in Childhood Cancers

Pathway to Discovery

Cancer is the leading cause of disease-related death among children in the United States.

While children and adults may experience some of the same types of cancer, the hurdles that children face can be very different. For example, children and adults may not be able to tolerate the same drugs or dosages; children can also respond differently to treatment and differ in their likelihood of remission.

Children with cancer are also less likely to have more than one disease at time, such as diabetes, heart disease, and lung disease that may complicate treatment in adults. On the other hand, children are more likely than adults to be affected by the short- and long-term side effects of cancer treatment.

Although significant progress has been made in treating childhood cancers over the past several decades, some cancers still do not respond to available treatments.

NCI spurs collaboration to address childhood cancers.

In 2005, NCI and the American Cancer Society joined forces to start addressing these concerns by hosting the "Childhood Cancer Targeted Therapeutics Workshop." Oncologists, researchers, cancer advocates, and representatives from drug companies and the Food and Drug Administration (FDA) were invited to discuss ways to find and develop new drugs for childhood cancers. Although much work was being done in childhood cancer research and many of NCI’s initiatives already had the research tools needed to find valid therapeutic targets, the workshop highlighted the need for collaboration between the public and private sectors.

In 2006, NCI and the Foundation for the National Institutes of Health formed a partnership to create the TARGET (Therapeutically Applicable Research to Generate Effective Treatments) initiative. TARGET involved a more coordinated approach to developing treatments for childhood cancer by:

• enhancing the research community’s understanding of the causes of childhood cancers
• advancing scientific discovery in childhood cancers
• rapidly translating information to improve early detection, diagnosis, and treatment of childhood cancers

TARGET studies five different childhood cancer types. 

For two years, TARGET successfully ran a pilot project to study two childhood cancers, acute lymphoblastic leukemia (ALL) and neuroblastoma. With additional funding from the American Recovery and Reinvestment Act in 2009, TARGET expanded to include several other cancers primarily found in children: acute myeloid leukemia (AML), osteosarcoma, and Wilms tumor.

These five cancer types were chosen based on the following:

• the need to improve treatment options for children with these cancers
• the ongoing NCI-supported work to study these tumors
• the availability of tissue samples for research

Enhancing Cancer Care

TARGET’s early success came from the ALL project team. The five-year survival rate for children with ALL has improved from 61 percent in the mid-1970s to about 90 percent today. However, there is still more to be done.

Although many children with ALL are cured with current treatments, one in five children still relapse. The prognosis after relapse is poor. Researchers wanted to reliably identify patients at a high risk of relapse and find better ways to treat them based on the molecular features of their diseases.

Gene mutations hold a clue.

Consequently, TARGET scientists studied the genes in children with ALL who are seen as being at high risk for relapse of ALL (high-risk ALL). They were looking for missing or extra pieces of chromosomes (the part of the cell that contains genetic information), measuring the expression of thousands of genes, and closely analyzing the sequences (or precise order) of genes that may play a role in ALL.

Researchers found that patients with high-risk ALL often have mutations in four key signaling pathways (or a group of molecules in a cell) that work together to control normal cell growth and function. One pathway in particular is known as the JAK signaling pathway. When it mutates, it can lead to overproducing abnormal blood cells.

The power of collaborative science emerges.

TARGET was key in bringing together many research groups from across the country, including the University of New Mexico, St Jude’s Children’s Research Hospital, University of California, New York University Cancer Institute, University of Florida College of Medicine, and the University of Colorado, Denver School of Medicine.

This group worked together to find that mutations in JAK genes were associated with deletion (or absence of a segment of DNA) in another gene called IKZF1, which is involved in B cell development (a type of white blood cell). They discovered that patients who had both a JAK mutation and IKZF1 deletion had a higher chance of relapse, death, or second cancer (78 percent) compared with only a JAK mutation (33 percent) or IKZF1 deletion (54 percent) alone.

Finding these genes also allowed researchers to identify new drugs that might work to alter their expression. In 2012, the journal Cancer Discovery reported that NCI "wasted no time bringing these findings to the clinic….[and] in September 2010 they began a phase I trial testing a drug called ruxolitinib that inhibits JAK proteins.... The ruxolitinib phosphate trial is one of the first tangible results from NCI’s TARGET initiative."

Science builds on science.

In another study, the TARGET ALL team from St. Jude Children’s Research Hospital reported finding another genetic alteration associated with high-risk ALL. A mutation in the IKZF1 gene causes a type of ALL known as Philadelphia chromosome-like ALL (Ph-like ALL). Children with Ph-like ALL have a higher rate of relapse compared with those with other types of ALL. These findings allow clinicians to better diagnose ALL and treat patients with drugs that focus on their specific type of cancer.

As Stephen Hunger, M.D., a professor of pediatrics at the University of Colorado and chair of the Children’s Oncology Group ALL Committee, told the NCI Cancer Bulletin in 2012, "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."

Turning Discovery Into Health

What TARGET researchers learned has influenced the design of clinical trials for childhood cancers. Studies now focus on small numbers of patients with specific mutations in their tumors. In general, TARGET is leading the way to new and exciting discoveries in childhood cancers.

An NCI Children’s Oncology Group clinical study and two drug industry-supported phase II trials are investigating the use of a JAK inhibitor to treat young ALL patients (1 to 21 years old) who have relapsed, whose tumors did not respond to previous treatments, and have a confirmed JAK mutation. This allows for a precision medicine treatment approach where patients are evaluated individually and treated based on the specific mutations in their particular tumors.

Research to Practice: NCI’s Role

NCI led the charge in helping the TARGET initiative become a reality. Responding to concerns raised by the public, private and government sectors, NCI worked to capitalize on existing resources and increase collaboration and effectiveness. A new research network was formed within NCI’s existing programs—The Cancer Genome Atlas project, the Cancer Therapy Evaluation Program, the Strategic Partnering to Evaluate Cancer Signatures project, and the Children's Oncology Group—to increase the speed of collaboration and sharing of ideas.

In addition, because of the National Institutes of Health’s open data sharing policy, all research that has come out of the TARGET initiative has been widely accessible to researchers, allowing for science to build upon itself.

Finally, NCI continues to invest in research to help improve existing treatments and to develop more effective treatment strategies that are less toxic for children with cancer. NCI's Center for Cancer Research plays a critical role in this effort.

Selected Resources

Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, Reaman GH, Carroll WL. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(14):1663-1669. [PubMed Central]

Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470-480. [PubMed Central]

Mullighan CG, Zhang J, Harvey RC, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2009;106(23):9414-9418. [PubMed Central]

National Cancer Institute. General Information About Childhood Acute Lymphoblastic Leukemia. 2013.

National Cancer Institue, Office of Cancer Genomics. TARGET, Therapeutically Applicable Research To Generate Effective Treatments. 2013.

Roberts KG, Morin, RD, Zhang J, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153-166. [PubMed Central]

Winstead ER. Genome study points to treatments for high-risk form of childhood leukemia. NCI Cancer Bulletin. 2012;9(17).

Zhang J, Mullighan CG, Harvey RC, et al. Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood. 2011;118(11):3080-3087. [PubMed Central]