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ARRA Investments in TARGET Cancer Treatment Initiative

Public Health Burden
Cancer is the leading cause of disease-related death among children and adolescents (1-19 years of age) in the United States. Each year, more than 12,000 new cases of cancer are diagnosed among individuals in this age group. In 2005, it was estimated that more than 2,000 children and adolescents died of cancer.

In recent decades, overall, we have witnessed dramatic advances in the treatment and management of childhood cancers. However, progress has not been uniform for all childhood cancer types, and some pediatric tumors remain difficult to treat. Moreover, current childhood cancer therapies can have serious short- and long-term side effects. Therefore, more-effective, less-toxic treatments are urgently needed. In adult cancers, recent successes have been achieved through the development and application of targeted therapies, such as imatinib mesylate (GleevecĀ®) and trastuzumab (HerceptinĀ®), but the targeted therapy revolution has not generally extended to childhood cancers. The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative is changing the dynamic of pediatric cancer research. TARGET will harness the power of genomic technologies to rapidly identify and validate targets in childhood cancers, ultimately leading to the development of targeted therapies for these diseases. The initial focus will be on cancers for which current treatments are inadequate.   ARRA funding is enabling an increase in the number of cancers studied under TARGET from two to at least five. The first cancers included under TARGET were high-risk acute lymphoblastic leukemia (ALL) and neuroblastoma. ARRA funds have allowed the addition of childhood acute myelogenous leukemia (AML), osteosarcoma, and Wilms tumor, which is a type of childhood kidney cancer. Examples of ARRA-funded research under TARGET include the following:
  • A project to study a gene called proliferation associated SNF2-like gene (PASG) and its protein product. The PASG protein is a member of a family of proteins that is involved in regulating chromosome structure, function, replication, and stability. Mutation of PASG has been identified in a high percentage of acute leukemias.1
  • A project to study the biology and clinical significance of mutations in a gene called FLT3 in AML. FLT3 is a component of signaling pathways important for the survival, proliferation and differentiation of hematopoetic cells.2
  • A project to validate newly identified mutations and signaling pathway alterations in childhood ALL as potential therapeutic targets and, upon validation, to implement testing for these markers in newly diagnosed patients. The results of this research could lead to the development of new targeted therapies for childhood ALL.3
  • A project to conduct an integrated genomic analysis of childhood ALL, which will enable: 1) the identification of recurring DNA copy number variations and the correlation of variations with effects on local and global gene expression patterns, 2) the identification of gene expression signatures that correlate with outcome, 3) a pathway analysis of genomic data to identify cellular pathways affected by genomic alterations, and 4) identification of sequence mutations in genes known to be mutated in pediatric ALL. The result of this analysis should increase our understanding of the biology of childhood ALL, increase our understanding of the genetic determinants of treatment outcome, and identify new targets for drug development.4
  • A project to develop genomic classifiers of progression-free survival that will allow the identification of subgroups among clinically defined high-risk stage IV neuroblastoma patients. The results should ultimately aid in guiding treatment and in the development of more effective therapies.5

  1. 3R01CA120535-03S1 -- Mechanisms of PASG-Mediated Senescence in Hematopoetic Development and Leukemia -- Arceci, Robert John (MD)
  2. 3R01CA114563-05S2 -- Biology and Prognostic implications of Flt3 mutations in AML -- Meshinchi, Soheil (WA)
  3. 1RC2CA148529-01 -- Targeted Therapies for Childhood Acute Lymphoblastic Leukemia -- Reaman, Gregory H. (CA)
  4. 1RC1CA145707-01 -- Genomic Analysis of Adolescent and Young Adult Acute Lymphoblastic Leukemia -- Mulligan, Charles G. (TN)
  5. 3R01CA060104-16S1 -- Clinical Correlative Studies of Neuroblastoma -- Seeger, Robert Charles (CA)

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