Personalized Medicine in Acute Myeloid Leukemia: Efficacy of a Novel Combination of Epigenetic Modifiers and a Tyrosine Kinase Inhibitor in Acute Myeloid Leukemia
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Date
2013-05
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The Ohio State University
Abstract
Acute myeloid leukemia (AML) is a heterogeneous blood cancer from which many patients die due to ineffective or toxic treatments; thus, there is a great need to develop more effective and personalized treatment options. Many AML patient samples display abnormal epigenetic regulation, and the Mixed Lineage Leukemia (MLL) gene, encoding for a histone H3 lysine 4 methyltransferase, is frequently mutated in AML. The partial tandem duplication (MLL-PTD) is found in ~5% of cytogenetically normal AML and correlates with a poor prognosis, especially when co-present with other mutations like the internal tandem duplication (ITD) of FMS-Like Tyrosine Kinase (FLT3-ITD, a receptor tyrosine kinase). In order to better test novel therapies in a preclinical model, we developed a murine model of spontaneous AML with a double knock-in of Mll-PTD and Flt3-ITD (referred to as Mll-PTD,Flt3-ITD) with 100% penetrance and a median survival 50-60 weeks. Since MLL-PTD associates with DNA hypermethylation in human AML patients, we analyzed the DNA methylome in our Mll-PTD,Flt3-ITD model and found an increase in the global DNA methylation index in leukemic mouse bone marrow compared to non-leukemic controls similar to the hypermethylation seen in human MLL-PTD leukemia. Using a transplant model of our Mll-PTD,Flt3-ITD mouse leukemia, a combination of epigenetic modifiers [Decitabine (5AD), a DNA methyltransferase inhibitor, and AR42, a novel histone deacetylase inhibitor] effectively targeted this AML in vivo, reducing leukemic burden, increasing tumor suppressor expression, and increasing survival. However, the mice still succumbed to leukemia. Since our mouse also has a Flt3-ITD mutation, we tested AC220 (a selective FLT3 inhibitor) in our mouse model. AC220 was shown to be a toxic single agent in our Mll-PTD,Flt3-ITD mouse model at doses required to produce killing of leukemic blasts. Since we saw toxicity with AC220 as a single agent, we asked whether combining epigenetic modifiers with AC220 would increase efficacy and allow for a less toxic dose. Preliminary ex vivo data in Mll-PTD,Flt3-ITD leukemic blasts demonstrated that a combination of epigenetic modifiers with AC220 reduced proliferation. Ultimately, our data suggests a combination therapy of epigenetic modifiers and a FLT3 inhibitor may effectively combat AML and provide a more “personalized” therapy for human patients with these mutations.
Description
2012 Barry M. Goldwater Excellence in Education Program Scholar
2012 American Society of Hematology Trainee Research Award
American Association for Cancer Research (AACR)-Thomas J. Bardos Science Education Award for Undergraduate Students
Cullen Trust for Higher Education Fellowship
2010 & 2011 Pelotonia Undergraduate Research Fellowship
2012 Denman Undergraduate Research Forum First Place
2013 AACR Eighth Annual Undergraduate Student Caucus and Poster Competition Second Place
2013 Denman Undergraduate Research Forum Second Place
2012 OSUWMC Annual Trainee Research Day Travel Award
2012 SOLAR Foundation Research Award
2011 Undergraduate Student Government Academic Enrichment Grant
2012 American Society of Hematology Trainee Research Award
American Association for Cancer Research (AACR)-Thomas J. Bardos Science Education Award for Undergraduate Students
Cullen Trust for Higher Education Fellowship
2010 & 2011 Pelotonia Undergraduate Research Fellowship
2012 Denman Undergraduate Research Forum First Place
2013 AACR Eighth Annual Undergraduate Student Caucus and Poster Competition Second Place
2013 Denman Undergraduate Research Forum Second Place
2012 OSUWMC Annual Trainee Research Day Travel Award
2012 SOLAR Foundation Research Award
2011 Undergraduate Student Government Academic Enrichment Grant
Keywords
Acute Myeloid Leukemia, Cancer Therapeutics, Epigenetics, Tyrosine Kinase Inhibitors, MLL-PTD, FLT3-ITD