Interrogation of glutathione biology in relapsed acute myeloid leukemia stem cells
Courtney Jones
PhDPrincess Margaret Cancer Centre, University Health Network
Project Term: October 1, 2022 - September 30, 2025
Acute myeloid leukemia (AML) is a devastating blood cancer. Most AML patients will initially respond to standard therapy; however, for many patients the disease recurs resulting in patient death. Consequently, there is an urgent need to develop new therapeutic strategies for relapsed AML patients. The objective of our proposal is to understand and target properties specific to relapsed AML cells with the overall goal of improving relapsed AML patient outcomes.
In the United States over 20,000 people are diagnosed each year with a devasting blood cancer called acute myeloid leukemia (AML). Most AML patients who receive therapy will initially respond; however, this response is often short-lived, and the leukemia comes back. Unfortunately, the majority of patients will succumb to this relapsed AML. Therefore, there is an urgent need to develop new therapeutic approaches for relapsed AML patients. Our preliminary data shows that relapsed AML cells are dependent on a molecule called glutathione (GSH). We show that GSH can bind to hundreds of proteins within AML cells which can change the function of the target proteins. This means that a single molecule, GSH, can regulate a wide range of biological functions within cancer cells. Importantly, inhibiting GSH does not affect normal blood cells suggesting that GSH could represent a therapeutic target with limited toxicity for patients. In this proposal, we will interrogate GSH biology and identify new strategies to target GSH in relapsed AML cells from patients. Specifically, we have three major objectives. First, we will determine differences in how GSH is made in AML cells isolated from patients at the time of diagnosis and relapsed to identify new potential druggable targets to block production of GSH. Further, we will determine which proteins GSH binds to in diagnosis and relapsed AML cells with the goal of uncovering relapse specific GSH bound proteins. We hypothesize, that relapse specific GSH bound proteins represent new targets for targeted therapy in relapsed AML. Finally, we will disrupt the molecules that regulate the binding of GSH to proteins and assess if these regulatory molecules represent new therapeutic targets for relapsed AML patients. Altogether, these three objectives will allow us to increase of understanding of GSH biology in AML and importantly, enable the discovery of new therapeutic targets for relapsed AML patients. To achieve these objectives, we will bring together a team of experts in the areas of translational AML studies as well as protein biology. Importantly, we will interrogate AML biology using primary AML specimens in advanced patient derived xenograft animal modeling which will ensure the clinical relevance our findings and enable the translation of our work into early phase clinical trials for relapsed AML patients.