Identification of Resistance Mechanisms and Novel Therapeutic Strategies in Tyrosine Kinase Inhibitor Resistant FLT3/ITD Acute Myeloid Leukemia
The mutation FLT3/ITD is common in acute myeloid leukemia (AML) and results in over-activation of cell signaling causing enhanced cell proliferation and survival. Patients with FLT3/ITD have a poor prognosis. The role of FLT3 inhibitors as targeted therapy is currently being evaluated in children and adults with AML. Despite an initial response, many patients relapse as the leukemic cells develop new mechanisms to survive and resist the effects of the targeted therapy. This group of patients has very few treatment options and very poor survival.
In anticipation and preparation of necessary therapeutic interventions in patients who fail targeted therapy, we developed FLT3-inhibitor resistant AML cells as a model of resistance that occurs in patients. We will also study leukemic cells from patients who relapsed after FLT3 inhibitor treatment. Using the cells and patient samples, we will define mechanisms contributing to resistance and identify new therapeutic options for patients who fail FLT3-targeted therapy. We will look at changes in the resistant leukemia cells at the genetic level. We will also silence individual genes to identify potential therapeutic targets that cause leukemic cell death. A high throughput drug screen composed of novel targeted agents will be used to identify alternative therapeutic strategies that are greatly needed in this group of patients.
"The Young Investigator grant from Alex’s Lemonade Stand Foundation allows us to continue the critical research of examining how resistance to targeted chemotherapeutic agents develops and investigating potential novel therapeutic strategies. Through my work, I hope to identify novel agents that will be effective in treating children with relapsed acute myeloid leukemia. The support from this grant will allow us to take critical steps to improve our ability to offer innovative treatments to children with leukemia." ~ Katherine Tarlock, MD