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 ofbone cancer that typically afflicts children and young adults, but it's alsoone that might pose a little less threat thanks to researchers at HuntsmanCancer Institute (HCI) at the University of Utah, who have shed new light onthe disease.

Their research, published online Aug. 31 in the journal Oncogene, shows that patients with Ewing's sarcoma whoexperience poor outcomes have tumors possessing high levels of a protein knownas GSTM4, which may suppress the effects of chemotherapy.

"Doctors and researchers have long known that certainEwing's sarcoma patients respond to chemotherapy, but others don't even thoughthey have the same form of cancer," says Dr. Stephen Lessnick, director ofHCI's Center for Children's Cancer Research, and holder a Jon and KarenHuntsman Presidential Professorship in Cancer Research. "Our research showsthat GSTM4 is found in high levels among those patients where chemotherapydoesn't seem to work. It's found in low levels in patients where chemotherapyis having a more positive effect."

These findings could also be considered a strong step in thedirection of advancing personalized medicine, as the researchers anticipatethese new insights could lead to a screening test that might reveal whichtherapies will be most effective for patients.

"GSTM4 doesn't seem to suppress the benefits of allchemotherapy drugs, just certain ones," Lessnick points out. "A GSTM4-basedtest could help to identify the best therapy for each individual patient."

In addition, he notes, this research from HCI could helpbolster drug discovery and development efforts that could lead to new drugsthat might suppress GSTM4 in certain patients to help enhance the effects ofGSTM4-susceptible drugs in those patients.

For this study, researchers focused on an abnormal proteinknown as EWS-FLI, which is found in most Ewing's sarcoma tumors, and theydiscovered hat EWS-FLI causes increased amounts of the GSTM4 gene to beexpressed in tumors. This, in turn, causes increased production of GSTM4'sproteins, previously unknown effect that led them to make the connectionbetween poor outcomes and high levels of GSTM4.

The discovery was made, the research team says, by focusingon repetitive DNA sequences called microsatellites, which are sometimesreferred to as "junk DNA" because they have not been thought to have a normalrole in the genome. But, by examining how EWS-FLI interacts with certainmicrosatellites, Lessnick and his team were able to identify GSTM4.

"Therapeutic approaches to Ewing's sarcoma consist of eithersurgery and/or radiation therapy to the primary site of disease, along withintensive systemic chemotherapy to eradicate micrometastatic disease," theresearchers noted in their article. "We reasoned that because GST enzymesdetoxify various reactive compounds, including therapeutic drugs, GSTM4 mightcontribute to the resistance profile of Ewing's sarcoma to chemotherapeuticagents."

Furthermore, the HCI researchers noted that their researchshows "the utility of combining transcriptional profiling, ChIP-chip andcomputational promoter analyses in the identification of target genes that areinvolved in oncogenesis and other cancer-relevant phenotypes, such as drugresistance. Indeed, our observation that GSTM4 has a role in resistance totherapeutic agents in this disease suggests a new paradigm for drug resistance:that key oncogenic events involved in tumorigenesis may directly regulate drugresistance programs, in addition to their more widely recognized role inpromoting oncogenic transformation."

Lessnick says the next step in research is to focus ontesting and treatments that may lead to better survival rates in patients.

"Personalized medicine is the next frontier in the battleagainst cancer," he stresses. "We now know all cancers are not the same. By focusingon how these proteins are expressed in individual tumors, we may soon be ableto offer the treatment that will work best for each patient, and that couldlead to higher cure rates."

Ewing's sarcoma is the second most common bone cancer inchildren 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 havesuffered a relapse.

The HCI research was supported by funds from the Terri AnnaPerine Sarcoma Fund, the Liddy Shriver Sarcoma Initiative, the SunbeamFoundation, the Huntsman Cancer Foundation and Alex's Lemonade StandFoundation.