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

Overall Mortality Rate for Childhood Cancers

Cancer remains 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 some types of childhood cancer over the past 5 decades, progress against other types has been limited. Moreover, when long-term survival is achieved, long-term adverse effects from the disease and/or its treatment may remain. Clearly, more research and newer and safer treatments for childhood cancer are needed.

NCI, therefore, has an extensive research portfolio that relates, directly or indirectly, to cancer in children and adolescents. The institute supports a broad range of biomedical research, including basic research to enhance our understanding of the fundamental mechanisms of cancer, clinical research to test new treatments for safety and effectiveness, and 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 percent of all new cases of cancer diagnosed in the United States each year. The small number of patients with any specific type of childhood cancer makes clinical trials to find more effective treatments challenging. As clinical trials are increasingly restricted to smaller, genomically defined populations of patients, collaboration among children’s cancer centers and a strong national clinical research program are essential to ensure that trials enroll sufficient numbers of participants.

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. Consequently, identifying opportunities for childhood cancer prevention may prove difficult.

In addition, childhood cancers generally differ in type and biological behavior from cancers diagnosed in adults. For example, carcinomas are more common in adults, whereas tumors of developing organs and tissues are more common in children.

Moreover, most childhood cancers lack mutations in genes that can be targeted by Food and Drug Administration (FDA)-approved agents or agents in development for adult cancers. Also, many childhood cancers have genomic drivers that are distinct from those that occur in adult cancers. These drivers often include activated genes that are challenging to target therapeutically (e.g., transcription factor genes). Thus, only a small number of targeted therapies are currently available for childhood cancers. A 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 are developing treatments for childhood cancers that are less toxic and mitigating the adverse effects, both acute and late, of current and previous therapies. The late effects of childhood cancer therapy can have profound physical, emotional, and other consequences, including a shortened life expectancy, for survivors. How to minimize and address these late effects to improve both the quality and the length of life of survivors is a research priority.

Furthermore, more information about drug metabolism in children, which varies with developmental age, is needed, as are better preclinical 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.

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, including the following:

  • The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program uses genomic approaches to catalog the full range of molecular changes in several childhood cancers 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 Pediatric Brain Tumor Consortium (PBTC) is a multidisciplinary cooperative research organization devoted to identifying better treatment strategies for children with primary brain tumors. Visit the consortium’s website.
  • 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. Childhood cancer survivors are at increased risk of developing second cancers and many other long-term health conditions commonly referred to as the “late effects” of cancer treatment.
  • The Pediatric Preclinical Testing Consortium (PPTC) systematically evaluates new agents in genomically characterized childhood cancer solid tumor and leukemia in vivo models. 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 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 dedicated to the study and treatment of 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.
5-Year Survival Rate For Selected Childhood Cancers

NCI-Supported Basic Research Improves Childhood Cancer Care

Virtually all progress against cancer in both children and adults has originated in basic research, often in areas that are not directly related to the disease. NCI, therefore, has traditionally made substantial investments in basic research because it recognizes that basic research provides the foundation and the raw materials for applied research.

As an example, the discovery of the CRISPR/Cas system for gene editing has revolutionized how childhood and adult cancer researchers study the genes that control cancer cell growth and survival. 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 cases of DIPG have a mutation in the gene for the histone protein H3.3 that prevents modification of the protein at specific amino acid. This mutation in H3.3 is thought to be a driver mutation for DIPG and is associated with aggressive disease and shorter survival.

Current and Future NCI Research Directions

Immunotherapies for Childhood Cancers

Immunotherapies are treatments that restore or enhance the immune system’s natural ability to fight cancer. In just the past few years alone, the rapidly advancing field of cancer immunology has produced several new methods for treating cancer.

One example is chimeric antigen receptor (CAR) T-cell therapy, which has been shown to induce sustained remissions in pediatric patients with acute lymphoblastic leukemia (e.g., as seen in clinical trials CTLO19 and CD19-CAR T). This therapeutic approach arose from decades of research on how the immune system works and how to manipulate it for clinical benefit. Early investigations by NCI scientists Lawrence Samelson and Richard Klausner on the structure of the T-cell receptor and the role this receptor plays in T cell activation, as well as the pioneering work of NCI’s Steven Rosenberg and his colleagues on an immunotherapy technique called adoptive cell transfer (ACT), helped pave the way for this major treatment advance.

The following are selected clinical trials of immunotherapy in pediatric and young adult patients that are currently underway in the NCI Center for Cancer Research’s Pediatric Oncology Branch:

  • A Phase I Trial of T Cells Expressing an Anti-GD2 Chimeric Antigen Receptor in Children and Young Adults With GD2+ Solid Tumors (NCT02107963)
  • Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma (NCT01593696)
  • Anti-CD22 Chimeric Receptor T Cells in Pediatric and Young Adults with Recurrent or Refractory CD22-expressing B Cell Malignancies (NCT02315612)

In addition, the Children’s Oncology Group and the Pediatric Brain Tumor Consortium are evaluating immunotherapy treatments for selected childhood cancers, including:

Molecularly Targeted Therapies

Brent Weston, M.D., and Harrison McKinion at UNC Lineberger Comprehensive Cancer Center

Harrison McKinion (right) was diagnosed with B-cell acute lymphoblastic leukemia in which the genes EBF1 and PDGFRB were rearranged. Brent Weston, M.D., of the UNC Lineberger Comprehensive Cancer Center, reports that Harrison has responded well to targeted therapy with imatinib and is expected to complete treatment in the spring of 2015.

Credit: Ginger McKinion

Molecularly targeted therapies are drugs or other substances that kill cancer cells by targeting specific molecules that are necessary for cancer cells to grow and survive. These therapies can be small molecule inhibitors, monoclonal antibodies, or antibody-drug conjugates.

The following are selected clinical trials of targeted therapy in pediatric and young adult patients that are currently underway in the NCI Center for Cancer Research’s Pediatric Oncology Branch:

In addition, the Children’s Oncology Group and the Pediatric Brain Tumor Consortium are evaluating targeted therapies for selected childhood cancers, including:

Finally, in 2016, NCI will launch the Pediatric Molecular Analysis for Therapy Choice (Pediatric MATCH) trial, which will provide opportunities to test molecularly targeted therapies in children with advanced cancers that have progressed on standard therapy. Tumor DNA sequencing will be used to identify those children whose cancers have a genetic abnormality for which either an approved or an investigational targeted therapy exists.

NCI Research Funding Decisions

For any given fiscal year, NCI does not make research funding decisions based on predetermined targets for a specific disease area or research category. Rather, the institute relies heavily on scientific peer review, in which highly trained outside scientists review research proposals and judge them on factors such as scientific merit, potential impact, and likelihood of success. Research proposals are also further evaluated by NCI leadership to consider additional factors, such as public health significance, scientific novelty, and overall representation of the research topic within the NCI portfolio. This intensive approach ensures that NCI supports the best science aligned with its mission.

FDA-Approved Drugs for Childhood Cancer

Since 1990, eight drugs have been approved by the FDA for childhood cancers, and data from NCI-sponsored clinical trials were used to support the approvals of five of these drugs (marked by asterisks):

Drug NameChildhood CancerYear Approved
Teniposide acute lymphoblastic leukemia 1992
Pegaspargase * acute lymphoblastic leukemia 1994 and 2006
Clofarabine acute lymphoblastic leukemia 2004
Nelarabine * T-cell acute lymphoblastic leukemia 2005
Imatinib * chronic myeloid leukemia
Philadelphia chromosome-positive acute lymphoblastic leukemia
2003
2013
Everolimus subependymal giant cell astrocytoma (SEGA) in both children and adults 2010 and 2012
Asparaginase Erwinia chrysanthemi * acute lymphoblastic leukemia 2011
Dinutuximab (monoclonal antibody ch14.18)* neuroblastoma 2015