Activating mutations in the FLT3 receptor tyrosine kinase are the most common molecular abnormality inAMI and are associated with significantly worse clinical outcomes. Several different small molecule FLT3nhibitors, which vary considerably in selectivity for FLT3, have been studied in AML patients, and most haveshown limited but consistent clinical activity. Our previous studies have demonstrated that FLT3 inhibitioncombined with chemotherapy leads to synergistic cytotoxic effects against FLT3 mutant AML cells, and thatFLT3 mutations are present in leukemia stem cells (LSCs). Preliminary results from ongoing clinical studiesof FLT3 inhibitors in relapsed AML patients suggest that chemotherapy followed by successful FLT3nhibition leads to clinical benefit. However, it is not known how selective for FLT3 the inhibitors should be,when and for how long in the course of therapy they should be given, and whether or not they are effectiveagainst LSCs. We have previously succeeded in pre-clinically modeling AML treatment regimensncorporating FLT3 inhibitors, and this proposal aims to extend this work in the context of several differentclinical trials. The broad goal of this proposal is to better understand how to incorporate FLT3 inhibition intoAML therapy so as to improve survival or cure rates for FLT3 mutant AML. The specific goals will be to useprimary leukemia cells from AML patients, including those enrolled on FLT3 inhibitor trials, to study theefficacy of selective and non-selective FLT3 inhibitors, alone and in combination with different sequences ofchemotherapy, against bulk leukemia cells and leukemia stem and progenitor cells using in vitro and animalmodels. Plasma from patients enrolled on FLT3 inhibitor trials will be used to study the efficacy of FLT3inhibition via measurement of FLT3 plasma inhibitory activity. The results of these studies using primaryblast samples and plasma from trial patients will be correlated with clinical outcomes.Lay description: A gene known as FLT3 is mutated in the leukemia cells of about one third of acute myeloidleukemia (AML) cases, and this subset of patients has a very poor prognosis compared to those who lackthis mutation. New drugs, known as FLT3 inhibitors, are being developed to target these FLT3 mutations.Our long-term goal is to learn how to incorporate these drugs into current treatment regimens in order toimprove the cure rate and prolong survival for AML patients with FLT3 mutations.
Showing the most recent 10 out of 487 publications
