Development of the Next Generation FLT3 Inhibitors for Pediatric AML and Infant ALL
Certain visible changes in the chromosomes and mutations in the genes correlate with good or bad prognosis in leukemia. FLT3 is one of the most frequently mutated genes in pediatric AML and also plays an important role in Infant ALL. In both types of pediatric leukemias the FLT3 protein acts as a gas pedal that is permanently pressed to the floor, telling cells to grow out of control. In order to send this signal, FLT3 needs to bind to an energy molecule called ATP.
My group was the first to clone the human FLT3 gene and to develop drugs that would block the binding of ATP to FLT3 so it could no longer send this signal. Since that time, a number of drug companies have developed drugs that target FLT3 and some are in clinical trials in adult and pediatric leukemias.
One of the problems limiting success of many of these drugs has been an inability to achieve sufficient blocking of the FLT3 growth signal. In addition, in some patients FLT3 developed resistance to some of the drugs that had previously achieved good inhibition of the growth signal. We have been testing a new FLT3 inhibitor that in preliminary data, appears to overcome some of the drawbacks that have limited the effectiveness of a number of the previous drugs. We want to explore the effectiveness of this drug against pediatric leukemias utilizing a number of models in order to validate its entry into pediatric AML and infant ALL clinical trials.