Targeting GSK3 in AML

Acute myeloid leukemiaAMLis one of the most common forms of leukemia in adults and despite advances in treatment theyear survival is less thanin adults and significantly lower in the elderlyThe remarkable success in treating one relatively uncommon subset of AMLacute promyelocytic leukemiawith all trans retinoic acidATRAillustrates the great promise for agents with greater efficacy and less toxicityUtilizing ATRAthe presumed cure ofof patients is possibleATRA s remarkable success stems from the fact that AML is a disease characterized by the arrest of differentiation of immature myeloid cellsATRA overcomes this block in differentiation by forcing leukemic cells to matureUnfortunatelyATRA does not work clinically forof AML patientsRecently we identified that targeting the kinase GSKis a promising strategy to induce AML differentiationparticularly in combination with ATRAUnfortunatelythere are no FDA approved specific GSKinhibitorsWe have identified a highly potent and specific GSKinhibitor that exhibits promise against AML in cell and animal modelsIn this proposalwe will assess the pharmacologic properties of this GSKinhibitorperform animal efficacy studiesand determine its effects on primary patient samplesIt is hoped that this work will lead to a new differentiation therapy that can improve the prognosis of patients with non APL leukemia 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