TARGETing Genomic Mutations in Childhood Cancers to make Therapeutic Advances
Among diseases, cancer is the leading killer of children in the United States, with leukemia and cancers of the brain and nervous systems accounting for more than half of the cases. Although there has been much progress in health outcomes for children diagnosed with cancer over the past few decades, there is still a tremendous need for more effective therapeutic and management approaches. Current treatments can have serious short- and long-term side effects, and new molecularly targeted therapeutics have been largely limited to the treatment of adult cancers.
The National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative aims to identify genetic markers in childhood cancers so that new and more effective therapies targeting these cancers' specific genetic mutations can be rapidly developed. Coordinated by the NCI Office of Cancer Genomics (OCG) and the Cancer Therapy Evaluation Program (CTEP), TARGET brings medical and research institutions together to identify valid targets for several pediatric cancers. Because the origins of childhood cancers are still largely unknown, this collaborative approach allows researchers to gain a comprehensive understanding of the underpinnings of pediatric cancers and their genetic triggers.
Expanding TARGET Research
With supplemental funding through the American Recovery and Reinvestment Act (Recovery Act), the TARGET initiative was expanded to include three additional pediatric cancers of study: acute myeloid leukemia (AML), osteosarcoma and Wilms tumor, as well as to continue research started in a pilot phase on acute lymphoblastic leukemia (ALL) and neuroblastoma. Neuroblastoma is a solid tumor that arises in immature nerve cells and often appears in the chest or abdomen. Half of all children presenting with the disease have the high-risk form, which has long-term survival rates of 50 percent or less. The current standard of care is known as "risk-directed," in which low-risk patients receive little or no cytotoxic therapy, while high-risk patients undergo an intensive treatment program that includes multiple types of chemotherapy and that lasts a little over one year.
"Currently, about half of all children with high-risk neuroblastoma can be cured, but receiving such intensive therapy as toddlers is very difficult," said John Maris, M.D., Chief of the Division of Oncology at the Children's Hospital of Philadelphia and Professor of Pediatrics at the University of Pennsylvania. As part of the TARGET initiative, Dr. Maris is leading a team (including investigators from Children's Hospital of Los Angeles and the NCI Center for Cancer Research) whose research efforts will uncover the alterations in the neuroblastoma genome that are important to the development of high-risk neuroblastoma and even more importantly, those that potentially can be treated with targeted therapies. "Children with neuroblastoma on average are 18 months old when they're diagnosed, and a huge issue is that almost all survivors have significant lifelong side effects from their treatment," said Dr. Maris. "The TARGET project is important because we both have to improve the effectiveness of our treatment as well as reduce the long-term side effects of the treatment."
The initial phase of the TARGET neuroblastoma project involved preliminary genomic characterization (defining the characteristics of the genome) in approximately 200 pediatric patients. The Recovery Act funds enable Dr. Maris' team to take the important next step to complete comprehensive genomic profiling of the neuroblastoma genome, including the use of second and third generation sequencing technologies, with the goal of discovering key mutations that drive this disease. Results obtained from the TARGET Initiative are made available to researchers through NCI databases. The Recovery Act-funded component of completing the sequencing and discovering mutations are expected within the next calendar year; however, the more detailed analyses and further translation of key findings to the clinic will continue to evolve for some time.
Targeting Genetic Changes
The ultimate goal of the TARGET initiative is to translate findings into new, more-specific treatment programs that will cause fewer side effects for these young patients. "One of the important contributions for the neuroblastoma TARGET project thus far has been its acceleration of understanding the role that mutations of the anaplastic lymphoma kinase (ALK) gene play in neuroblastoma, supporting rapid translation of this finding into the clinic," noted Malcolm Smith, M.D., Ph.D., Associate Branch Chief of Pediatrics, CTEP at NCI. "The ALK discovery is an encouraging example of what TARGET may be able to achieve in finding other therapeutic targets to improve treatment strategies for young neuroblastoma patients."
Although TARGET focuses on childhood cancers, significant therapeutic discoveries could potentially extend to adult cancers. Likewise, experimental therapies currently under investigation in adult clinical trials may prove beneficial when applied to pediatric cancers displaying similar genomic changes. For example, Dr. Maris' group was able to quickly translate the ALK finding in neuroblastoma patients into a Phase I pediatric clinical trial using a drug targeting ALK abnormalities that occur in adult lung cancer patients. Dr. Maris leads the neuroblastoma clinical trials activities of the Children's Oncology Group, thereby facilitating the seamless integration of promising TARGET findings directly into the nationwide NCI-supported clinical trials program for children with cancer.
Stimulating Broader Research
In addition to accelerating the research timeline, the Recovery Act award will have a multiplier effect. "We expect that the TARGET discoveries will lead to multiple investigator-initiated research projects both on the basic side as well as on the translational side," said Dr. Smith. "Because of discoveries made through TARGET, these future projects will address much more insightful and fundamental research questions about the genes and signaling pathways that control neuroblastoma growth and survival."
Early on in his career, Dr. Maris became interested in neuroblastoma and was convinced that cancer was a disease of the genome. He believed that critical insights needed to design rational therapies could be made by discovering the genes that caused the cancer. In his opinion, the TARGET initiative and ARRA funding are more important and more relevant than ever. "It is something that came at exactly at the right time in terms of an unmet need, technology being available, and we were able to put together the right team of scientists to address that unmet need. So I view it as a once in a career opportunity to really make a huge difference."
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