The discovery of a specific pattern of gene expression linked to multiple-drug resistance of leukemic cells is giving researchers crucial information into why standard therapies fail to cure some children with acute lymphoblastic leukemia (ALL). This finding, from investigators at St. Jude Children’s Research Hospital, could lead to development of drugs that would overcome that resistance.
This new finding helps to explain why about 20 percent of children with ALL, the most common form of childhood cancer, are not cured with the same drug therapy that cures the remaining 80 percent of children with this disease. A report on the study that produced this new information appears in the April issue of Cancer Cell.
Drug resistance is a major cause of treatment failure, and the biochemical mechanisms responsible for de novo resistance are largely unknown. De novo resistance means that the resistance is “built into” the leukemic cells through a particular pattern of gene expression, rather than acquired through genetic mutation during treatment. Cross-resistance to multiple drugs suggests a poor prognosis and likely involves biochemical mechanisms that are different from those linked to single-drug resistance.
The investigators sought to identify the specific pattern of gene expression in ALL cells that is linked to de novo cross-resistance to four widely used antileukemic agents, and to determine how those genes affected treatment outcome.
“The identification of a particular genetic expression pattern linked to cross-resistance takes us a significant step forward in understanding why treatment fails to cure certain children who initially looked like good candidates for standard chemotherapy,” said William E. Evans, Pharm.D., St. Jude director and member of St. Jude Pharmaceutical Sciences. “The results also give us crucial information into treatment failure that could help us design more effective treatments for the children our current treatment strategies fail to cure.”
Evans is senior author of the Cancer Cell report.
The ALL cells used in the study were isolated from the bone marrow or the blood of patients with newly diagnosed disease who were being treated at St. Jude, the Dutch Childhood Oncology Group at the Sophia Children’s Hospital in the Netherlands or the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia at the Children’s University Hospital in Hamburg, Germany.
Using pharmacogenomics techniques to assess gene expression levels in ALL cells, researchers identified 45 genes closely linked with leukemic cells’ ability to resist treatment by at least two of the most widely used antileukemic drugs. The drugs tested were prednisolone, vincristine, asparaginase and daunorubicin. The team also identified 139 genes that are closely linked to a previously unknown and unexpected type of drug resistance in which leukemic cells are resistant to asparaginase (ASP) but sensitive to vincristine (VCR). This “discordant” type of resistance (resistance to one drug and sensitivity to another) was associated with a poor response in children who had this pattern of gene expression.
Cross-resistant patients had significantly worse outcomes as a group. Among patients whose ALL cells were cross-resistant, only 53 percent had a five-year, relapse-free survival compared to 91 percent of those whose ALL cells were cross-sensitive to all the drugs.
Among patients whose ALL cells were ASP-sensitive plus VCR-resistant, the five-year, relapse-free survival rate was 93 percent, compared to 56 percent among patients whose ALL cells were VCR sensitive and ASP resistant. The genes linked to discordant resistance included many that are involved with the function of ribosomes, the cell’s protein-making factories.
“This discordant resistance has not previously been described by other researchers,” said Meyling H. Cheok, Ph.D., one of the postdoctoral fellows who did much of the work on this project. “The fact that it is associated with genes involved with protein synthesis gives us an important clue to the basis of this type of drug resistance.”
Other authors of the paper are Sanne Lugthart (who contributed equally with Meyling Cheok on the work), Monique L. den Boer, Amy Holleman and Rob Pieters (Sophia Children’s Hospital, The Netherlands); Wenjian Yang, Cheng Cheng, Ching-Hon Pui and Mary V. Relling (St. Jude); and Gritta E. Janka-Schaub (Children’s University Hospital, Germany).
This work was supported in part by the Sophia Children’s Hospital Foundation and the Dutch Cancer Foundation, the Pediatric Oncology Foundation, the Nijbakker-Morra Foundation, and the Renee Vogel Stipendium (The Netherlands); the National Institutes of Health, a Cancer Center Support Grant, the American Cancer Society and FM Kirby Clinical Research Professorship and ALSAC.