Current Research and Scholarly Interests
Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow that is rapidly fatal within months if untreated. Even with aggressive treatment, including high dose chemotherapy and bone marrow transplantation, five-year overall survival rates range between 30-40%. A growing body of evidence indicates that not all cells in this cancer are the same, and that there is a rare population of leukemia stem cells (LSC) that are responsible for maintaining the disease. These findings have led to the idea that in order to cure this cancer, the LSC must be eliminated, while at the same time sparing the normal blood forming stem cells within the bone marrow.
The overall goal of the research is to identify molecular and genetic differences between human AML stem cells and their normal counterparts, and then to develop therapeutic strategies directed against these targets. We have used a bioinformatic analysis to identify genes and pathways preferentially expressed or activated in LSC. From this analysis, we identified a number of cell surface protein markers that are more highly expressed on AML LSC compared to their normal counterparts. We then determined that one of these protein markers, CD47, contributes to leukemia development by blocking the ingestion and removal of leukemia cells by cells of the immune system. Most significantly, we determined that blocking monoclonal antibodies directed against CD47 targeted LSC and depleted leukemia in mouse pre-clinical models.
Currently, our major focus is the development of therapeutic antibodies directed against CD47 and/or additional protein markers present in much larger amounts on the external surface of the LSC compared to the normal blood forming stem cells. It is our hope that we will develop a clinical grade therapeutic antibody for the treatment of AML that will be investigated in clinical trials at the Stanford Cancer Center.