Elucidating and Targeting the Cell Surface Proteome of Pediatric T Cell Acute Lymphoblastic Leukemia
Acute Lymphoblastic Leukemia is the most common childhood cancer. T cell ALL is an especially aggressive subtype of ALL which affects up to 20% of children with ALL. Up to 25% of children with T-ALL will relapse and succumb to chemotherapy resistant disease. Leukemia survivors experience long-term side effects that permanently affect their quality of life, both physically and mentally. Thus, there is an urgent need to develop targeted therapies to not only improve survival but reduce long-term side affects associated with current treatments. Immunotherapies and small molecule therapeutics, which have seen great success in treating other subtypes of ALL, are currently lacking for children with T-ALL. A major hurdle is the inability to find targets for therapy that spare healthy cells and efficiently eradicate disease. Thus, it is imperative that research works to identify biological characteristics that differ between healthy cells, T-ALL cells from patients who are cured, and T-ALL cells from patients who resist therapy. Recently, we identified inflammation as an underlying biological signature identifying patients at elevated risk of treatment failure. Here, we propose to identify T-ALL proteins associated with inflammation to reveal novel therapeutic targets to improve pediatric patient outcomes.
Project Goal:
Here, we propose to identify proteins uniquely expressed on the surface of cells from T cell acute lymphoblastic leukemia (T-ALL) patients. Specifically, we will be comparing the cell surface proteins between patients who show evidence of inflammation at diagnosis versus those who do not as we recently identified inflammation as being associated with poor treatment responses. After identifying proteins uniquely expression on these inflammatory T-ALL cells, we will utilize genetic editing to delete these proteins from the surface of T-ALL cells to see if they are necessary for survival. When we identify specific proteins that play a role in leukemic cell survival, we will test the ability of antibodies, a type of protein which can bind and block the function of other proteins, to kill leukemic cells. Thus, our project seeks to identify proteins associated with inflammatory T-ALL patient cells that are important for disease survival and progression. Importantly, we will perform preclinical trials to determine if they represent clinically actionable therapeutic targets.
