Grant: Operating Grant

Acute myelogenous leukemia (AML) is thought to be caused by a primitive leukemia stem cell in the bone marrow which maintains the disease and prevents cure due to its survival after chemotherapy and bone marrow transplant. This malignant stem cell has a unique feature in that it displays on its surface, a protein called CD123. We have been studying a new approach to eliminating these leukemia stem cells using antibodies that bind to CD123 that are linked to a radioisotope called indium-111. This radioisotope is very toxic to the leukemia cells if it is transported to the nucleus of the cells. We have taken advantage of the fact that the radioactive antibodies are naturally taken up by cells displaying CD123 and also that they can be encouraged to localize in the nucleus of the cells by modification with small peptides that have nuclear localization signals. Already, we have shown that these radioactive antibodies are indeed taken up by leukemia cells and transported to the nucleus where the indium-111 has proven moderately toxic to the cells. We have also shown that these radioactive antibodies localize specifically at sites of leukemia in mice inoculated with AML cells. In the proposed research, we will study approaches to enhance the toxicity of these radioactive antibodies towards leukemia cells, and examine their ability to decrease leukemia in AML engrafted mice as well as study their normal tissue toxicities. If successful, our research will lead to a new targeted radiation treatment for leukemia which could be tested in a Phase I clinical trial. Ultimately, our goal is to improve the long-term outcome for 4 out of 5 patients with AML who cannot currently be cured and rarely survive more than a few years.