MEMPHIS, Tenn., Scientists have identified new genetic alterations underlying a high-risk subtype of the most common childhood cancer that could be effectively targeted with existing leukemia therapies.
The study focused on a subtype of acute lymphoblastic leukemia (ALL) known as Philadelphia chromosome-like ALL (Ph-like ALL). This subgroup accounts for as much as 15 percent of childhood ALL that is associated with a high risk of relapse and a poor outcome. The genetic changes driving the disease were previously unknown for about half of all patients with Ph-like ALL. The work identified new alterations in genes that regulate how cells grow and proliferate. St. Jude Children's Research Hospital investigators led the research, which appears in the online edition of the journal Cancer Cell.
Investigators also showed that the leukemia cells were sensitive to several targeted therapeutic agents, imatinib and dasatinib, which are already being used against other leukemias, but not this subtype. The findings suggest patients with Ph-like ALL may benefit from the addition of these drugs to current chemotherapy regimens.
"One of the next steps will be to continue work on laboratory tests to rapidly identify patients whose cancer cells carry these alterations and to develop clinical trials to test targeted therapies," said Charles Mullighan, M.D., Ph.D., an associate member of the St. Jude Department of Pathology, and a corresponding author of the study.
The study involved sequencing the RNA of cancer cells from 15 patients with Ph-like ALL and whole genome sequencing of two of those patients. Whole genome sequencing involves deciphering the DNA molecule, which contains the complete set of instructions for building and maintaining life. Cells use RNA to translate DNA's instructions into proteins. Sequencing RNA provides a snapshot of gene activity in a cell.
The work was part of the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which aims to use genomics to identify therapeutic targets and spur development of more effective treatments for childhood cancer. NCI is part of the National Institutes of Health. The collaboration included investigators fromSt. Jude, the Children's Oncology Group and the British Columbia Genome Sciences Center.
"This work is another example of how a detailed analysis of the genetic changes present in cancer cells can identify the changes that are critical for cancer cells to escape normal growth controls and allow them to resist standard chemotherapy treatments, but also serve as an Achilles' heel that can be attacked by drugs targeted at these genetic changes. It's also important to recognize that work like this is only possible because patients with ALL and their parents agreed to participate in clinical trials and linked studies about the genetics of cancer," said Stephen Hunger, M.D., a professor of pediatrics at the University of Colorado, chairman of the Children's Oncology Group ALL Committee and a corresponding author of the study.
ALL is the most common childhood cancer. While approximately 90 percent of newly diagnosed ALL patients are cured with current treatments, only 63 percent of children with Ph-like ALL are alive and cancer-free after five years.
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