Childhood Cancers Research

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Phineas Sandi, participated in an NCI clinical trial

Phineas Sandi, shown here on his first day of kindergarten, participated in an NCI clinical trial that tested genetically engineered T cells to treat acute lymphoblastic leukemia. He was in remission within 11 days of starting the trial and remains free of cancer.

Credit: Kristina Sandi

Why Research Is Critical to Progress against Childhood Cancer

Cancer is the leading cause of death from disease among children and adolescents in the United States. Although substantial progress has been made in the treatment of several types of childhood cancer over the past 5 decades, progress against other types has been limited. Even when long-term survival is achieved, many survivors of childhood cancer may experience long-term adverse effects from the disease or its treatment. Clearly, more research is needed to develop new, more-effective, and safer treatments for childhood cancer.

NCI has a number of programs that address childhood cancers specifically, and many of the institute’s other research programs are applicable to children with cancer even if they aren’t focused specifically on pediatric cancers. The institute supports a broad range of biomedical research that is relevant to this population, including:

  • Basic research to enhance our understanding of the fundamental mechanisms of cancer
  • Clinical research to test new treatments for safety and effectiveness
  • Survivorship research to reduce the long-term adverse effects of cancer and its treatment

Challenges in Childhood Cancer Research

One challenge in conducting research on childhood cancer is that cancers in children and adolescents are relatively uncommon. Childhood cancers represent less than 1% of all new cases of cancer diagnosed in the United States each year. As clinical trials are increasingly restricted to smaller numbers of patients who are defined by the molecular characteristics of their tumors rather than where the tumors originated in the body, collaboration among children’s cancer centers and a strong national clinical research program will continue to be essential to ensure that trials enroll sufficient numbers of participants to produce meaningful results.

Overall Mortality Rate for Childhood Cancers

Another challenge is that very little is known about the causes of childhood cancers. A small percentage of cancers in children and adolescents can be linked to inherited genetic abnormalities or exposures to diagnostic or therapeutic radiation, but the role of environmental exposures, including infectious agents and toxic chemicals, is unclear. As a result, identifying opportunities to prevent childhood cancer may be difficult.

In addition, the types of cancers children develop, and the biology of those cancers, generally differ from those of cancers diagnosed in adults. For example, tumors of developing organs and tissues (such as retinoblastomas in the eye and osteosarcomas in bone) are more common in children.

Moreover, most childhood cancers have relatively few genetic alterations, and they generally lack the targets for treatments that have been developed and approved for adult cancers. Moreover, drugs that target signaling pathways that are active in some adult cancers might be difficult to use in children, given that many of these signaling pathways are essential for normal development.

In fact, childhood cancers are often driven by genetic alterations that are distinct from those that occur in adult cancers. These drivers, fusion genes that result from chromosomal translocation, produce “fusion oncoproteins,” for which few treatments have been developed to date. Another contributing factor to the small number of targeted therapies for childhood cancers is that the rarity of these diseases has been an impediment to commercial drug development.

Additional challenges in childhood cancer research are developing new treatments that are less toxic and cause fewer adverse effects (both acute and late) than current treatments and developing interventions to mitigate the adverse effects of both current and future treatments. The late effects of childhood cancer therapy can have profound physical, emotional, and other consequences for survivors, including a shortened life expectancy. How to minimize and address these late effects to improve both the quality and the length of life of survivors is a research priority.

More information about drug metabolism in children, which varies with developmental age, is also needed, as are better laboratory and animal models for screening and testing drugs for potential use in children and adolescents. The optimal use of radiation therapy in treating childhood cancers also needs to be defined so that efficacy is maintained or increased while long-term side effects are reduced.

Basic Research Drives Progress against Childhood Cancer

Virtually all progress against cancer in both children and adults has its origins in basic research, often in areas that are not directly related to the disease.

As an example, the discovery of the CRISPR/Cas system for gene editing has revolutionized the study of genes that control cancer cell growth and survival in both childhood and adult cancers. This discovery came from basic research in microbiology on the mechanisms by which bacteria resist infections by viruses.

Another example had its origins in basic research on proteins called histones, which are DNA-binding proteins that provide structural support for chromosomes and help control the activity of genes. Scientists spent years investigating how these proteins are modified in the cell nucleus and the role of histone modifications in controlling when and to what extent genes are expressed. The findings of this research became immediately relevant to a type of pediatric brain tumor called diffuse intrinsic pontine glioma (DIPG) when it was discovered that most DIPG tumors have a mutation in the gene for the histone protein H3.3 that prevents a specific modification of the protein. This mutation in H3.3 is thought to be a driver mutation for DIPG and is associated with aggressive disease and shorter survival.

How NCI Programs Are Making a Difference in Childhood Cancer

NCI recognizes that children and adolescents are not just small adults and that specialized treatments tailored to childhood cancers are needed. Therefore, NCI supports an array of programs specifically to advance childhood cancer care, and has renewed these initiatives and programs over numerous funding periods. Some of these programs include:

  • The Pediatric Brain Tumor Consortium (PBTC) is a multidisciplinary cooperative research organization devoted to identifying better treatment strategies for children with primary brain tumors.
  • The Childhood Cancer Survivor Study (CCSS) is examining the long-term adverse effects of cancer and cancer therapy on approximately 35,000 survivors of childhood cancer who were diagnosed between 1970 and 1999.
  • The Pediatric Preclinical Testing Consortium (PPTC) systematically evaluates new agents in genomically characterized models of childhood cancer. The primary goal of the PPTC is to develop high-quality preclinical data to help pediatric oncology researchers identify agents that are most likely to show significant anticancer activity when tested in the clinic against selected childhood cancers.
  •  The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program uses genomic approaches to catalog the molecular changes in several types of childhood cancer to increase our understanding of their pathogenesis, improve their diagnosis and classification, and identify new candidate molecular targets for better treatments. The related Cancer Genome Characterization Initiative includes genomic studies of various pediatric cancers that often do not respond well to treatment.
  • The Hyperactive RAS Specialized Programs of Research Excellence (SPOREs) focus on developing better treatments for neurofibromatosis type 1 and related cancers in children, adolescents, and young adults.
  • The Pediatric Oncology Branch (POB) in NCI’s Center for Cancer Research conducts high-risk, high-impact basic, translational, and clinical research on childhood cancers.
  • The Children's Oncology Group (COG), which is part of NCI's National Clinical Trials Network (NCTN), develops and coordinates pediatric cancer clinical trials that are available at more than 200 member institutions, including cancer centers throughout the United States and Canada. In addition to conducting traditional late-phase clinical trials, the COG has established a Phase 1 and Pilot Consortium to conduct early-phase trials and pilot studies so new anticancer agents can be rapidly and efficiently introduced into pediatric cancer care.
  • NCI held two workshops in 2015, as part of the NCI Provocative Questions Initiative, to identify questions that address gaps in the pediatric oncology research field. NCI will release program announcements and funding opportunities for these pediatric oncology provocative questions, which are intended to generate innovative approaches to childhood cancer research challenges.
  • The Pediatric MATCH precision medicine trial, which will be led by COG and is expected to launch in 2017, will provide an important opportunity to test molecularly targeted therapies in children with advanced cancers who have few other treatment options. The genomic data captured in the trial will serve as an invaluable resource for researchers seeking to understand the genetic basis of pediatric cancer.
5-Year Survival Rate For Selected Childhood Cancers