AML differentiation therapy

Acute Myeloid LeukemiaAMLis a broad range of disorders that all have the defining feature of leukemic cells with a maturation arrestDespite the fact that AML is the most common form of leukemia in adultsthere have been no changes in standard therapy in overyearsThe traditional chemotherapeutics used exhibit both high toxicity and poor efficacy with a median survival in patients over the age ofof less than one year with onlyof these patients surviving two yearsInstead of directly cytotoxic agentsagents that induce the maturation of AML cells offers a therapeutic approach that targets the primary pathophysiology of the diseaseWe previously identified a plant derived alkaloid as a promising AML differentiation agentOur lead compound exhibits high potency on AML cells and promising activity in a mouse model of human AMLMechanistic studies suggest that this agent leads to perturbation of mitochondrial metabolism through inhibition of the enzyme thioredoxin reductaseIn this proposal we propose to develop our lead compound by identifying ideal routes and schedules of dosing to miceconfirming the activity and mechanism of action of our lead compound in mouse models of human AML and identifying the optimal AML patients for this therapyIt is hoped that this work will lead to a more efficacious and safer therapy for AML patients This project is highly relevant to public health as its main objective is to lead to the development of a novel therapy for patients with AML that is both efficacious and has lower toxicity than existing therapyAs the current therapeutics have low efficacy in patients with AMLthere is a significant need for new therapies