NATIONAL CANCER INSTITUTE
Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative
1. What is the TARGET?
The TARGET (Therapeutically Applicable Research to Generate Effective Treatments) Initiative is using the power of modern genomics technologies that allow scientists to greatly expand the scope of their search for new genetic targets that lie at the heart of childhood cancers. This comprehensive approach allows cancer researchers to gain a global picture of the tumor and its causes with the aim of bringing a new era of therapies that target a cancer’s specific genetic mutations and pathways, to positively impact patient outcomes and bring hope to the children and families who face the devastating burden of this disease.
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2. What organizations are participating in TARGET?
TARGET research on acute lymphoblastic leukemia (ALL) is funded and collaboratively managed by NCI’s Office of Cancer Genomics, Cancer Therapy Evaluation Program and Strategic Partnering to Evaluate Cancer Signatures Program. These NCI organizations are conducting collaborative research with Children’s Oncology Group, St. Jude Children’s Research Hospital and the University of New Mexico Cancer Center. The neuroblastoma research is funded and collaboratively managed by NCI’s Office of Cancer Genomics, Cancer Therapy Evaluation Program, and Center for Cancer Research, with research collaboration from Children’s Hospital of Philadelphia, Center for Childhood Cancer's Biopathology Center, and the University of California at Los Angeles.
Click here to learn more about the TARGET Collaborators.
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3. What cancer types have been chosen for study in TARGET and why?
TARGET researchers are investigating the genomic changes associated with acute lymphoblastic leukemia (ALL) and neuroblastoma, two common types of childhood cancer. Together, neuroblastoma and ALL account for over 3,000 pediatric cancer diagnoses each year. While dramatic improvements in survival have been observed over the last several decades for both ALL and neuroblastoma, the pace of these improvements has slowed over the past decade. More research is needed to identify valid therapeutic targets, advance the understanding of the molecular basis of these cancers and treatment failure, and develop more effective therapeutics and treatment plans based on the genetic makeup of a patient’s disease.
ALL and neuroblastoma were selected based on their prevalence and the availability of clinically annotated, collections of tumor samples that met TARGET’s strict scientific, technical, and ethical requirements. These collections were identified through a Childhood Cancer Biospecimens TARGET Initiative Request for Information (RFI) issued in 2007.
The plan is to add additional cancers as the opportunities arise.
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The information generated by these three focus areas help form the framework for subsequent efforts directed toward the development of targeted drug therapies to improve the treatment of acute lymphoblastic leukemia (ALL) and neuroblastoma.
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5. What are some of the basic steps in taking a genomic alteration found as part of the TARGET project and "translating" it to the clinic?
Genomic characterization and resequencing efforts provide scientists with a list of candidate genes that are associated with the cancers being studied in TARGET. Genes provide the specific instructions for a cell to make proteins and these proteins do most of the “work” in a cell. When there is a change in the instructions coming from the gene through a change in the DNA, the cell may get the wrong instructions and be unable to make protein correctly. As a result, the protein may not work in the way it should. Since proteins control how a cell “works”, changes in proteins can ultimately impact how a cell behaves.
Once scientists verify that the genomic change is associated with cancer cells, the impact of this specific change is studied in the laboratory. These functional studies seek to confirm that the identified genetic changes cause a change in the cell’s behavior consistent with cancer. For example, the change makes the cells divide too often, divide too quickly or survive when they normally would not.
The most promising targets are then studied to determine if there is a drug or novel molecule that could be used to prevent the changes in a cell caused by the genetic mutation. This testing is usually started in cells in the laboratory and followed up in animal models long before it is ever brought to the clinic for use in humans.
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6. What will TARGET mean for children with cancer and their families?
For many years the world benefitted from a series of dramatic improvements in the management and treatment of pediatric cancers. More recently, however, the rate of improvement in patient outcomes has slowed. The medical community has seen the success of molecularly targeted therapies for some forms of cancer through drugs like Gleevec but, until now, targeted treatment evolution has had limited impact in the childhood cancer setting.
The TARGET Initiative is helping to accelerate the pace by which these targets are discovered for pediatric cancers and is facilitating the development of effective new treatment plans. Moreover, TARGET is effectively prioritizing experimental drugs used in adult clinical trials for use in pediatric cancers, with the ultimate goal of making significant strides in the outcomes for children with cancer. One of the goals of the TARGET initiative is to identify specific drugs with a greater potential for success, with fewer side effects and higher rates of success.
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7. Will the data generated by TARGET be publicly available?
Yes, the data generated by TARGET is accessible via the TARGET Data Portal, allowing scientists to access information during the course of the project as it becomes available. This Cancer Biomedical Informatics Grid® (caBIG®) compliant Web-based Data Portal is completely publicly accessible, allowing academic researchers, biotechnology firms and pharmaceutical companies to access, examine and evaluate the data. caBIG® is an information network enabling all constituencies in the cancer community to share data and knowledge.
The goal of TARGET data sharing via the Portal is to facilitate the discovery of therapeutic targets for ALL and neuroblastoma and catalyze the translation of the findings for clinical applications that reduce the burden of these childhood cancers. Data analyses by many researchers will increase the likelihood of discovering potential therapeutic leads that might be missed were the data not available to the larger research community.
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8. What sorts of genomic changes will TARGET look for?
In order to draw an integrated picture of the alterations associated with childhood cancer, TARGET is investigating a variety of genomic features. Technologies employed in TARGET research can identify regions of genetic deletion or amplification (also known as copy number alterations), changes in gene expression levels, and DNA mutations at the single nucleotide level.
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9. How will genes of interest be chosen in TARGET?
Genes of interest will be chosen for sequencing based on changes identified in gene expression, structure, and deletion or amplification via advanced genomic technologies.
Once chosen, the role and relevance of these genes in tumor development will be validated with a variety of approaches that allow investigators to study these genes in the laboratory.
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10. How will TARGET leverage NCI’s existing investments in other large-scale genomic projects?
TARGET is making extensive use of data, tools, and approaches generated by projects like the Children’s Oncology Group (COG), NCI’s Cancer Therapy Evaluation Program (CTEP), caBIG®, and Strategic Partnering to Evaluate Cancer Signatures (SPECS) initiatives. The Cancer Genome Atlas (TCGA) and caBIG® have invested heavily in the development of bioinformatic tools applicable to the approaches and goals of TARGET. The SPECS program aims to deepen our understanding of cancer "signatures," the genetic (and epigenetic) data that distinguish one cancer type from another. The COG has an extensive and well-annotated repository of tumor samples and is currently serving as TARGET’s primary source of biological materials for analysis. The CTEP program is effectively prioritizing experimental drugs used in adult clinical trials for use in pediatric cancers.
Click here to learn more about these related initiatives.
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11. Are there ethical and legal implications since TARGET studies children/pediatric cancers?
NCI recognizes the importance of addressing the ethical and legal implications of this project. Because patient privacy protection is the highest priority and of the utmost concern to NCI and TARGET collaborators, human subjects protection and data access policies have been implemented to protect the privacy and confidentiality of patient data. The TARGET project team is adhering to strict data access standards to ensure that data available through the public data Portal cannot be linked back to a specific individual.
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12. What are the main challenges faced by TARGET?
A major challenge for cancer research, especially for the molecular characterizations of cancer-associated changes, is the complexity of the group of diseases we call cancer. Different cancer types originate from a wide range of genetic mutations and molecular mechanisms. This means that even two patients who receive the same diagnosis are likely to have distinct causes of their disease at the level of DNA. Specifically, different genetic changes might be responsible for the development of the same cancer. This is why one patient might respond well to a specific treatment and the other might not.
This heterogeneity, or variation, between tumors means that scientists need to compare many individual tumors with the same diagnosis in order to be able to make conclusions. Despite the prevalence of cancer in our society, finding a sufficient number of tumor samples to perform studies of this magnitude is a significant challenge for this project and others of its kind. Learn more about what NCI is doing to overcome this challenge through its Office of Biorepositories and Biospecimen Research.
Additionally, the balance between open data access and patient privacy is also a high priority for the TARGET Initiative, due to the nature of the population TARGET is studying. Data policies have been developed to ensure data access while protecting the privacy of patient information, along with the appropriate handling of intellectual property. Strict patient privacy standards include the inability to aggregate data to generate a dataset unique to an individual patient.
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13. What has the TARGET Initiative discovered to date and what are the implications of these data?
Researchers have discovered a novel genetic marker that predicts a high likelihood for relapse in children with high-risk acute lymphoblastic leukemia (ALL). Changes in the gene IKZF1, also called IKAROS, were strongly associated with relapse in the study of 221 children with high-risk leukemia. This result has been replicated in a second group of 258 children with high-risk ALL. The study found that the leukemia cells from patients with IKAROS alterations were more resistant to standard therapy and may benefit from a more aggressive treatment.
This is important because treatment failure is common for high-risk ALL, yet the biology of treatment resistance has been poorly understood. These TARGET research findings advance our understanding of the molecular basis of ALL and may help guide a more personalized approach to treatment. By using molecular tests to identify the genetic markers in ALL patients, physicians may be better able to assign patients to appropriate therapies. The ability to identify patients with different risks is critical to ensure that patients with high-risk ALL receive treatment of appropriate intensity, while low-risk cases are spared unnecessary toxicity of higher doses. Until now, there has not been a good marker for predicting treatment outcomes.
TARGET researchers also identified mutations in a class of genes called the JAK kinases. These mutations appear to activate, or “turn-on”, the kinases, which are thought to activate pathways involved in cell growth and proliferation related to cancer. In the TARGET study, JAK mutations frequently occurred alongside mutations in IKAROS; the majority of the tumors with a JAK kinase mutation also had a mutation in IKAROS. Importantly, almost 80% of patients with mutations in both the JAK kinase gene and IKAROS relapsed within 4 years compared to only 23% of patients with neither mutation. This is of particular interest because drugs that target JAK kinases and inhibit their function are already in clinical trials, and may be used as potential treatment for a subset of ALL patients.
Molecular characterization and information like that about the connection between specific mutations in genes like IKAROS and the JAK kinases and leukemia relapse, are important first steps in translating genomic information to medical decisions, including decisions about patient risk and specific treatment options.
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