Targeting metabolism in AML

Acute myeloid leukemia (AML) is the most common type of acute leukemia affecting adults, but unfortunately there has been no change in standard therapy for most patients in over 40 years. Traditional chemotherapeutics exhibit poor efficacy in patients over the age of 56, with a median survival of less than one year and only 20% surviving two years. The development of novel therapies for AML is urgently needed. We previously identified a plant derived alkaloid as a promising agent that impaired the growth and survival of AML cells. Through medicinal chemistry efforts, we have identified a series of securinine analogues with high potency and promising activity in mouse models of human AML. We have identified that these compounds inhibit the enzyme thioredoxin reductase and that this leads to direct and marked effects on metabolism. In this grant, we will investigate how thioredoxin reductase functions as a major regulator of cancer cell metabolism through pharmacologic and genetic studies. In addition, we will perform lead optimization chemistry to identify securinine analogues with improved pharmacologic properties and test them in mouse models of human AML. It is hoped that this work will lead to improved therapies for AML and a novel understanding of how thioredoxin reductase can directly regulate cancer cell metabolism.