Childhood Cancers Research

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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 imatinib therapy and is expected to complete treatment in the spring of 2015.

Why Research is Critical to Progress against Childhood Cancer

NCI recognizes the importance of research that specifically addresses pediatric cancers and has an extensive research portfolio that relates directly, or indirectly, to cancers in children and adolescents. The Institute supports a broad range of biomedical research that extends from basic science, which enhances our understanding of the fundamental mechanisms of cancer, to clinical research, which tests new therapies for safety and effectiveness.

In the United States in 2015, an estimated 10,380 new cases of cancer will be diagnosed among children from birth to 14 years, and more than 1,000 children will die from the disease. Although pediatric cancer death rates have declined by nearly 70 percent over the past four decades, cancer remains the leading cause of death from disease among children. Despite this progress, better and safer treatments for childhood cancers are needed.

How NCI Programs Are Making a Difference in Childhood Cancer

NCI recognizes that children are not just small adults and that specialized treatments tailored to pediatric cancers are needed. NCI supports the following programs specifically to advance childhood cancer care:

  • 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 TARGET program has already identified many new mutations and chromosomal abnormalities associated with pediatric cancers; these studies have led to two clinical trials with new drugs against childhood tumors.
  • The Children's Oncology Group (COG), which is part of the 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.

    The COG will also conduct a new Pediatric Molecular Analysis for Therapy Choice Program (Pediatric MATCH) trial, which will provide opportunities to test molecularly targeted therapies in children with advanced cancers and who therefore have few treatment options. The Pediatric MATCH trial will enroll children with cancers that have progressed on standard therapy. Sequencing of the DNA in tumor samples will be used to identify children whose cancers have a genetic abnormality for which either an approved or investigational targeted therapy exists. For those children for whom no molecularly appropriate therapy is available, immunotherapeutic approaches will be considered.
  • The Childhood Cancer Survivor Study (CCSS) is studying the long-term 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 secondary cancers and many other long-term health conditions commonly referred to as “late effects” of cancer treatment.
  • The Pediatric Preclinical Testing Program (PPTP) systematically evaluates new agents against laboratory and animal models of childhood solid tumors and leukemias. The primary goal of the PPTP 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.
Karen Kinahan, M.S., R.N., and Julia Stepenske

Karen Kinahan, M.S., R.N., (left), director of the STAR program at Northwestern University’s Lurie Comprehensive Cancer Center, which provides long-term care for adult survivors of childhood cancers, and Julia Stepenske, childhood cancer survivor and stem-cell transplant nurse, at an event celebrating the STAR program’s 10th anniversary.

NCI Supports Basic Research to Improve Childhood Cancer Care

Virtually all progress against cancer—in both children and adults—has been founded in basic research, often in areas not directly related to the disease. An understanding of basic scientific principles in the realms of biology, chemistry, physics, and other disciplines is essential for continued progress. NCI, therefore, strongly supports basic scientific research in addition to cancer-oriented translational and clinical research.

The following are some examples of how NCI’s support of basic scientific research is leading to clinical advances against cancer:

  • Immunotherapies for childhood cancer: The current success of immunotherapies, such as chimeric antigen receptor (CAR) T-cell therapy in pediatric patients with acute lymphoblastic leukemia (e.g., as seen in clinical trials CTLO19 and CD19-CAR T), stems from an understanding of basic immunology that has been built over the last several decades. Part of this success is due to the discovery by NCI researchers Lawrence Samelson and Richard Klausner of the intracellular domain of the T-cell receptor (TCR) that makes TCR signaling possible. In addition, the pioneering work by NCI’s Steven Rosenberg and his colleagues in immunotherapy using adoptive cell transfer (ACT) has also paved the way for today’s success.

    Another example of the critical role NCI has played in developing immunotherapies for childhood cancer is the monoclonal antibody dinutuximab (mAb ch14.18), which was approved by the Food and Drug Administration (FDA) in early 2015 for use in the first-line treatment of children with high-risk neuroblastoma. Dinutuximab targets a molecule called GD2 on the surface of neuroblastoma cells. The FDA approval was based on findings from an NCI-sponsored randomized phase III clinical trial conducted by the COG. NCI not only sponsored this pivotal phase III trial, it also supported the basic research that led to dinutuximab’s creation in the mid-1980s and it manufactured sufficient quantities of the antibody for the trial through the NCI Biopharmaceutical Development Program at Frederick, Maryland. NCI later entered into a Cooperative Research and Development Agreement with a biotechnology company under which the company assumed responsibility for manufacturing dinutuximab and moving it through the steps required for regulatory approval.

    Selected immunotherapy trials in pediatric patients, underway in the Pediatric Oncology Branch at NCI’s Center for Cancer Research, include:

    1. A Phase I Trial of T Cells Expressing an Anti-GD2 Chimeric Antigen Receptor in Children and Young Adults With GD2+ Solid Tumors (NCT02107963)
    2. Anti-CD19 White Blood Cells for Children and Young Adults With B Cell Leukemia or Lymphoma (NCT01593696)
    3. Anti-CD22 Chimeric Receptor T Cells in Pediatric and Young Adults with Recurrent or Refractory CD22-expressing B Cell Malignancies (NCT02315612)
  • C-MET—from understanding its function to cabozantinib: Today, studies are underway with NCI and other federal support to evaluate the drug cabozantinib as a potential therapy for children and young adults with cancer. These investigations include studies of central nervous system tumors, melanoma, and thyroid cancers; osteosarcoma and Ewing sarcoma; and plexiform neurofibromas in adolescents and young adults with neurofibromatosis. Cabozantinib is a small molecule that inhibits the activity of enzymes called tyrosine kinases—proteins that speed up chemical reactions in the body. Certain tyrosine kinases are more active in some types of cancer cells, and blocking their activity may help keep the cancer cells from growing.

    More than 20 years of basic, preclinical, and clinical research ultimately led to the FDA approval of cabozantinib in 2012 to treat metastatic thyroid cancer, and to its ongoing study in children and adults with cancer.

    How did these clinical research efforts reach the point they are at today? Developing a detailed understanding of the C-MET signaling pathway was a critical step. Cabozantinib targets the tyrosine kinases C-MET, RET, and VEGFR2, and C-MET is active in all of the cancer types noted above. NCI support was key in linking C-MET to the development of cancer and in identifying it as an important target for cancer therapeutics.

    In 1984, scientists at NCI, the Dana-Farber Cancer Institute, the Wistar Institute, and Litton Bionetics first identified a dysfunctional form of C-MET that was caused by a chromosome rearrangement. Two years later, NCI investigators and researchers from Litton Bionetics, who were operating under an NCI contract, provided one of the first pieces of evidence that C-MET has the ability to initiate the growth of cancers that are derived from epithelial cells, or cells that line the internal and external surfaces of the body. This discovery highlighted the great potential of C-MET as a target for anticancer therapy. NIH also funded grants for preclinical animal studies that were instrumental in showing that inhibiting C-MET impairs cancer cell growth and metastasis. This work made significant contributions to understanding the mechanisms of C-MET function, serving as the foundation for further discovery and targeting efforts.

    No one could have anticipated that the basic research discovery of C-MET in the early 1980s would lead to small molecule inhibitors such as cabozantinib that show promise for treating so many different types of cancer.

    Additional information for the trials noted above:

    1. A phase I study of cabozantinib (XL184) in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: A Children’s Oncology Group phase I consortium trial (NCT01709435) (see also: http://meetinglibrary.asco.org/content/135300-144)
    2. A Phase II Study of Cabozantinib (XL l84) for Plexiform Neurofibromas in Subjects with Neurofibromatosis Type I Age 16 years or greater (NCT02101736)
    3. Cabozantinib-s-malate in Treating Patients With Relapsed Osteosarcoma or Ewing Sarcoma (NCT02243605)
  • Immunotoxins for Cancer Therapy—a 45-year NCI Investment: NCI researcher Ira Pastan and his colleagues developed the very first immunotoxins—immune system molecules coupled to powerful toxins—to selectively kill cancer cells. They have been able to successfully treat adults and children with certain blood cancers using immunotoxins that contain the bacterial toxin Pseudomonas exotoxin A (PE).

    Dr. Pastan first came to NIH in 1959, and joined NCI in 1970 to establish the Laboratory of Molecular Biology within NCI’s intramural research program. After many years of research leading to foundational discoveries in the area of gene regulation, Dr. Pastan and his team shifted their focus to studying immunotoxins in 1990. As they explored whether it was possible to develop new agents that could selectively kill cancer cells, they also tackled the problem of finding a way to deliver the toxins to tumor cells. Dr. Pastan made several important improvements, using genetic engineering, to make smaller, more nimble immunotoxins that could be produced inexpensively and in large quantities.

    Over time, his laboratory has developed several PE-containing immunotoxins in collaboration with the Pediatric and Medical Oncology branches at NCI. One new immunotoxin, moxetumomab pasudotox or HA22, targets a molecule called CD22 on B-cell cancers in adults and children.

    Moxetumomab pasudotox is now being tested in a number of trials for children and young adults with certain leukemias or lymphomas:

    1. Moxetumomab Pasudotox (CAT-8015, HA22) in Children With B-lineage Acute Lymphoblastic Leukemia and Minimal Residual Disease Prior to Allogeneic Hematopoietic Stem Cell Transplantation (NCT02338050)
    2. A Phase 2, Multicenter Study in Pediatric Subjects With Relapsed or Refractory Pediatric Acute Lymphoblastic Leukemia (pALL) or Lymphoblastic Lymphoma (NCT02227108)
    3. CAT-8015 in Children, Adolescents and Young Adults With Acute Lymphoblastic Leukemia or Non-Hodgkin's Lymphoma (NCT00659425)
  • Targeting additional cell signaling pathways: Understanding basic cell biology is essential in finding ways to stop cancer cell growth and metastasis. By learning about cellular signaling pathways and how they are altered in cancer, we can develop drugs that can be used to therapeutically target these alterations.

    For example, the anaplastic lymphoma kinase (ALK) signaling pathway has been studied extensively since it was first described in 1994. This pathway was found to be important in embryonic nervous system development. Scientists also determined that mutations in the ALK gene play a fundamental role in a variety of cancers, including non-small cell lung cancer (NSCLC), anaplastic large-cell lymphoma, and familial neuroblastoma. The drug crizotinib had been developed to target C-MET, but it was also known to inhibit ALK. After much study, the FDA approved its use for the treatment of patients with NSCLC in 2013. Crizotinib is now being tested in numerous clinical trials across the country in pediatric patients with cancers that have ALK mutations.

    Examples of NCI-sponsored trials of crizotinib in pediatric and young adult patients:

    1. Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma (NCT01979536)
    2. Crizotinib and Combination Chemotherapy in Treating Younger Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma (NCT01606878)
    3. Crizotinib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma (NCT00939770)
    Similarly, decades of extensive research have shown that components of the Hedgehog (Hh) signaling pathway drive the growth of a variety of cancers, including basal cell carcinoma (BCC) of the skin. In 2012, the FDA approved vismodegib, a drug that inhibits the Hh pathway, for the treatment of BCC. Since this pathway has also been linked to medulloblastoma, a common malignant brain tumor in children, vismodegib has been tested in pediatric patients. Without a basic understanding of the Hh pathway, these types of advances could not be made.

    Examples of NCI sponsored trials of vismodegib in pediatric and young adult patients:

    1. Vismodegib in Treating Younger Patients With Recurrent or Refractory Medulloblastoma (NCT01239316)
    2. GDC-0449 in Treating Young Patients With Medulloblastoma That is Recurrent or Did Not Respond to Previous Treatment (NCT00822458)

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.

NCI's commitment to cancer research demonstrates the urgency of making progress for all patients, including children with cancer, and for the many at risk of developing cancer. They deserve nothing less.