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Issue 7 – June 2012
Featured Researcher
Sarcomas: An Ongoing Challenge in Pediatric Oncology
Paul Meltzer, M.D., Ph.D.
Dr. Paul Meltzer researches sarcomas and other cancers as Senior Investigator and Chief of the Genetics Branch in the Center for Cancer Research at the National Cancer Institute. As a TARGET investigator, Dr. Meltzer uses genomics analyses to study a type of sarcoma called osteosarcoma.
Pediatricians understand that children are not little adults. This is apparent across a range of medical fields, including pediatric oncology. Fortunately, cancers are rare in the pediatric population. When they do occur, the majority are quite different from the common cancers of adults. Brain tumors, Wilms tumors, neuroblastomas and sarcomas are the dominant types of solid tumors (as opposed to blood cancers) diagnosed in pediatric patients. Sarcomas are tumors of the connective tissues of the body such as muscle or bone. Sarcomas that typically manifest in children include rhabdomyosarcoma (related to muscle), osteosarcoma (related to bone), and Ewing’s sarcoma, a mysterious tumor possibly derived from early connective tissue stem cells. In addition to these three, there are numerous other tumors occurring at an even lower frequency. Although there is some variation, the majority of pediatric sarcomas are aggressive tumors which call for intense multimodality therapy including surgery, radiation and chemotherapy. While these rigorous treatments are often helpful and can be curative, many pediatric sarcoma patients cannot be cured with current approaches. Progress in improving outcomes for this difficult group of tumors remains an important priority for pediatric cancer research.
Researchers studying these diseases are examining sarcoma tumor genomes in hopes of finding keys to unlock their underlying biology and open new possibilities for treatment. Previous research has shown that sarcomas (both adult and pediatric) broadly fall into two categories based on the degree and types of abnormalities in their genomes. The first category, exemplified by Ewing’s sarcoma and alveolar rhabdomyosarcoma, contains specific fusion genes composed of segments from two genes which have been juxtaposed by a chromosome translocation. Often these are transcription factors which are thought to drive tumor growth by disturbing the normal pattern of gene expression. Dozens of fusion genes are known in various sarcomas, and new ones are discovered with some regularity. The second category of sarcomas, exemplified by osteosarcoma, lacks fusion genes and typically has a highly rearranged genome with many structural and numerical changes distributed across the genome. This category also tends to occur in older patients and contain mutations in the tumor suppressor gene TP53.
The ability to profile genome structure and function through the advent of powerful new sequencing technologies and microarray methods has opened up the possibility of providing a truly comprehensive description of the sarcoma genome. There are a number of specific questions which investigators hope to answer using this modern approach. For example, do translocation-bearing sarcomas carry additional mutations which contribute to tumor growth? What mutations occur in genetically complex tumors, such as osteosarcoma? Are there recurrent mutations in genes or pathways which will reveal the mechanisms of tumor formation? It is hoped that addressing these questions could lead directly to new treatments for sarcomas. Supporting this notion, previous research revealed that most adults with the sarcoma gastrointestinal stromal tumor (GIST) have tumors with activating mutations in one of the receptor tyrosine kinases, KIT or PDGFRA. By targeting these kinases with therapies in the appropriate individuals, survival rates have significantly increased for GIST patients. Additionally, activating mutations in the growth factor receptor FGFR4 were recently discovered in some cases of rhabdomyosarcoma. This raises the possibility of developing novel therapies for patients with this disease, as therapeutic strategies targeting this receptor are currently being explored. Even in the absence of identified targets, such as growth factor receptors, describing sarcoma genomes will provide a firm basis for future research on these diseases.
At this time, large-scale sequencing projects are underway for the pediatric sarcomas: rhabdomyosarcoma, Ewing’s sarcoma and osteosarcoma. Under the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, osteosarcoma is being intensively investigated. In addition to sequencing tumor genomes and transcriptomes, investigators are also studying the pattern of gene copy number alterations, the status of DNA methylation, and the expression of micro-RNAs in the tumor genome. Interestingly, alterations in micro-RNAs, a fascinating new class of small RNAs which regulate the expression of protein-coding genes, are emerging as important regulators of tumor biology in cancers, including osteosarcoma. Taken together, the various genomics methods of the TARGET initiative will build on the understanding of how gene expression is altered in osteosarcoma and how it contributes to tumor development. The results of these studies will fill critical gaps in our knowledge and are sure to alter thinking about the best way to approach the development of new treatments not just for osteosarcomas, but for other pediatric sarcomas as well.
