Defining mechanisms of sensitivity and resistance to PI3K gamma inhibition in AML
Andrew Lane
PhD, MDDana-Farber Cancer Institute
Project Term: October 1, 2024 - September 30, 2027
The goal of our laboratory is to discover, study, and the translate new leukemia therapies to the clinic. In this project, we are studying a signaling pathway, called PI3 kinase gamma, that we believe is important in patients with AML and might lead to new treatments using drugs that target its activity.
Patients with AML remain in great need of better therapies that are more active and better tolerated. Some patients with AML have mutations in their leukemia cells that connect them to approved therapies, such as those that target mutated FLT3 or IDH. However, most patients do not have targeted therapy available to them, including those who initially respond to chemotherapy or targeted treatments but then their disease progresses. In preliminary work for this project, we performed experiments where we tested blocking all the genes in the genome in leukemia cells and found that a specific subset of AML is dependent on a pathway called PI3 kinase gamma. This was very interesting because PI3 kinase gamma had never been studied previously in leukemia. However, PI3 kinase gamma drugs are already being studied in the lab and even in clinical trials because they help solid tumor patients’ cancers respond better to immune-activation drugs. Therefore, we were excited to learn more about PI3 kinase gamma in leukemia because we think we can quickly apply the existing drugs to new treatments for AML if we understand the pathway better. Here, we propose to study samples from many patients with AML to better understand which ones may be most sensitive to treatment with these drugs that block the PI3 kinase gamma pathway so that we might best select patients for this therapy. We also want to test which drugs are best to combine with PI3 kinase inhibitors. Finally, we will also study what activates the pathway in leukemia cells and how that activation protects leukemia cells or makes them grow faster. Our expected output of the project is that we will be ready to design and perform a clinical trial using new drugs that target PI3 kinase gamma in patients with AML.