Investigating the dependency for protein synthesis in Venetoclax/Azacitidine-resistant acute myeloid leukemia
Ana Vujovic
PhDUniversity of Colorado Denver, Anschutz Medical Campus
Project Term: July 1, 2024 - June 30, 2027
Relapsed and/or refractory acute myeloid leukemia (AML) display resistance to Venetoclax and Azacitidine (Ven/Aza) with approximately one third of patients demonstrating upregulated protein synthesis. This proposal will investigate the mechanism(s) underlying the dependence of Ven/Aza-resistant AML on protein synthesis as well as the functional consequences of targeting this pathway. Successful completion of these studies will provide novel insights into Ven/Aza resistance mechanisms.
The goal of this application is to advance our understanding and treatment of acute myeloid leukemia (AML), a form of blood cancer. Despite efforts to develop therapies, AML patient outcomes remain poor. As such, there is a critical need for treatment options that eradicate the disease. AML has a small population of cells called cancer stem cells and a larger population of cells that make up the bulk of the disease. Cancer stem cells are the root of the disease, like that of a root of a tree. Current therapies can eliminate the bulk of AML, analogous to cutting the trunk of a tree, but just like the roots of a tree can grow a new tree, the cancer stem cells are able to persist through treatment and give rise to the disease again. The Jordan laboratory and others have significantly contributed to characterizing biological features that are unique to these cancer stem cells in AML and identifying how these features can be exploited therapeutically. Previous work from our lab has shown that cancer stem cells in AML rely on a specific process to make energy, and when this process is impaired, these cells cannot survive. Our lab has found that the combination therapy consisting of Venetoclax and Azacitidine, Ven/Aza, targets this energy process and eradicates cancer stem cells in AML. Still, most patients relapse with disease that is resistant to Ven/Aza. Therefore, understanding and targeting the specific processes that allow the cancer stem cells in AML to be resistant to Ven/Aza therapy is of paramount importance for improving AML treatments and patient outcomes. We have observed that patients whose AML relapses after treatment with Ven/Aza have increased processes related to protein production, highlighting this as a potential vulnerability of cancer stem cells in AML. Our laboratory is uniquely equipped to lead research investigations that are aimed toward understanding these processes in AML cancer stem cells that are resistant to Ven/Aza, as proposed in this application. To address this, we will use AML patient specimens to investigate global changes in protein- and energy-related processes in AML cancer stem cells that are resistant to Ven/Aza treatment as well as test the efficacy of impairing these processes with novel therapies. Successful completion of this work will provide insights into the vulnerable features of AML cancer stem cells and potential treatment strategies to target these features to improve AML patient outcomes.