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U. of Utah findings in so-called ‘junk DNA’ provide new hope for childhood bone cancer
SALT LAKE CITY—Ewing's sarcoma is an often-deadly form of bone cancer that typically afflicts children and young adults, but it's also one that might pose a little less threat thanks to researchers at Huntsman Cancer Institute (HCI) at the University of Utah, who have shed new light on the disease.
Their research, published online Aug. 31 in the journal Oncogene, shows that patients with Ewing's sarcoma who experience poor outcomes have tumors possessing high levels of a protein known as GSTM4, which may suppress the effects of chemotherapy.
"Doctors and researchers have long known that certain Ewing's sarcoma patients respond to chemotherapy, but others don't even though they have the same form of cancer," says Dr. Stephen Lessnick, director of HCI's Center for Children's Cancer Research, and holder a Jon and Karen Huntsman Presidential Professorship in Cancer Research. "Our research shows that GSTM4 is found in high levels among those patients where chemotherapy doesn't seem to work. It's found in low levels in patients where chemotherapy is having a more positive effect."
These findings could also be considered a strong step in the direction of advancing personalized medicine, as the researchers anticipate these new insights could lead to a screening test that might reveal which therapies will be most effective for patients.
"GSTM4 doesn't seem to suppress the benefits of all chemotherapy drugs, just certain ones," Lessnick points out. "A GSTM4-based test could help to identify the best therapy for each individual patient."
In addition, he notes, this research from HCI could help bolster drug discovery and development efforts that could lead to new drugs that might suppress GSTM4 in certain patients to help enhance the effects of GSTM4-susceptible drugs in those patients.
For this study, researchers focused on an abnormal protein known as EWS-FLI, which is found in most Ewing's sarcoma tumors, and they discovered hat EWS-FLI causes increased amounts of the GSTM4 gene to be expressed in tumors. This, in turn, causes increased production of GSTM4's proteins, previously unknown effect that led them to make the connection between poor outcomes and high levels of GSTM4.
The discovery was made, the research team says, by focusing on repetitive DNA sequences called microsatellites, which are sometimes referred to as "junk DNA" because they have not been thought to have a normal role in the genome. But, by examining how EWS-FLI interacts with certain microsatellites, Lessnick and his team were able to identify GSTM4.
"Therapeutic approaches to Ewing's sarcoma consist of either surgery and/or radiation therapy to the primary site of disease, along with intensive systemic chemotherapy to eradicate micrometastatic disease," the researchers noted in their article. "We reasoned that because GST enzymes detoxify various reactive compounds, including therapeutic drugs, GSTM4 might contribute to the resistance profile of Ewing's sarcoma to chemotherapeutic agents."
Furthermore, the HCI researchers noted that their research shows "the utility of combining transcriptional profiling, ChIP-chip and computational promoter analyses in the identification of target genes that are involved in oncogenesis and other cancer-relevant phenotypes, such as drug resistance. Indeed, our observation that GSTM4 has a role in resistance to therapeutic agents in this disease suggests a new paradigm for drug resistance: that key oncogenic events involved in tumorigenesis may directly regulate drug resistance programs, in addition to their more widely recognized role in promoting oncogenic transformation."
Lessnick says the next step in research is to focus on testing and treatments that may lead to better survival rates in patients.
"Personalized medicine is the next frontier in the battle against cancer," he stresses. "We now know all cancers are not the same. By focusing on how these proteins are expressed in individual tumors, we may soon be able to offer the treatment that will work best for each patient, and that could lead to higher cure rates."
Ewing's sarcoma is the second most common bone cancer in children and adolescents, and the five-year survival rate is considered poor, at about 30 percent, if the cancer has spread by the time it is diagnosed. There is an even poorer prognosis for survival rates among patients who have suffered a relapse.