Cotargeting oncogenic protein translation and apoptosis in acute myeloid leukemia
Yoke Seng Lee
PhDThe Brigham and Women’s Hospital
Project Term: July 1, 2024 - June 30, 2026
The focus of my research is to evaluate the efficacy of and to unravel the molecular mechanisms underpinning a novel drug combination in AML targeting oncogenic protein translation and apoptosis. We will utilize genetic perturbation and other orthogonal approaches, including in vitro and ex vivo assays, and in vivo AML PDX models. The goal of my research is to transform the clinical management of AML patients, particularly for relapsed and difficult-to-treat subgroups.
Acute myeloid leukemia (AML) is an aggressive blood cancer and the most common acute leukemia in adults, with an estimated 20,380 new cases in the US in 2023. Despite advances in new therapies, the 5-year survival remains at only 27%. There is a clear unmet need for more effective treatments in AML. The long-term goal is to improve AML patient outcomes by identifying new therapeutic approaches. This project seeks to understand the synergistic killing of AML cells by targeting two biological pathways - protein synthesis and control of cell death, through the use of a novel drug combination. The specific aims are (1) to identify key factors responsible for driving AML cell death and (2) to demonstrate efficacy of this drug combination compared to standard therapy using healthy and diseased human bone marrow cells and a mouse model of AML. In this project, I will use AML cell lines (cells adapted to grow in a lab environment) and human bone marrow samples to determine the effects of both drugs when used alone or in combination. I will also use genetic and protein-based methods to uncover key genes and proteins driving AML cell death. The animal model used here is transplanted with human AML cells, also known as a patient-derived xenograft model. This model is both gold standard and highly clinically relevant to patients who do not respond to current treatment or have relapsed despite initial response. Overall, I anticipate that proteins driving major signaling and survival pathways in the cell to be decreased in response to the drug combination. I also expect to uncover key proteins involved in pathways of protein synthesis and control of cell death that explain the synergistic AML cell killing observed. Finally, I expect the novel drug combination to be superior to standard therapy when evaluated in the mouse model of AML. This work will lay the foundation on which prospective clinical trials could be conducted to evaluate the efficacy of the drug combination in humans. This drug combination could also have clinical benefit in patients who developed resistance to existing therapies or failed to respond to multiple treatment options, thereby revolutionizing clinical management of AML.