Targeting Signaling Pathways that Confer Cytarabine Resistance in Pediatric AML

Baylor College of Medicine, Houston, TX

Nearly 40% of children with acute myeloid leukemia (AML) relapse, and many of them die of progressive AML. Current treatments still use the same old drugs, including cytarabine. Patients with detectable AML after one cycle of treatment have a very high risk of relapse. This residual leukemia is the focus of our proposal. Our goal is to identify and block the processes that allow some AML cells to survive treatment. Interactions between AML cells and the bone marrow environment support survival of a small number of AML cells, but scientists have not yet figured out how to overcome this problem. Studies with AML patients and with mice that received cytarabine have shown that residual AML cells are changed in ways that favor cytarabine resistance. Our experiments confirm that AML cells from mice treated with cytarabine have higher activity of a survival protein, STAT3, than AML cells from mice treated with placebo. We hypothesize that resistance processes are enhanced in AML cells that survive cytarabine, and blocking these processes reduces residual disease and prolongs survival. We will engineer changes in AML cells to interrupt the processes that promote cytarabine resistance, and compare the effectiveness of cytarabine in mice with engineered AML cells compared to normal AML cells. Also, we will test drugs that block resistance processes in mice with human AML. This research will lead to novel strategies to overcome cytarabine resistance so that more children will be cured.