Baylor College of Medicine
Project Term: July 1, 2019 - June 30, 2024
Our lab is focused on identifying unique features that distinguishes acute myeloid leukemia (AML) stem cells from normal blood-forming stem cells. The cells that make more AML cells than others are called AML stem cells, and these cells need to be eradicated to achieve deep therapeutic responses. We believe targeting metabolism may achieve this goal and found strategies to target AML stem cell metabolism without harming normal stem cells. We hope that our study will lead to improved therapies against AML targeting metabolism to achieve deep remission with little toxicity.
Acute myeloid leukemia (AML) is a cancer of the bone marrow and the blood that leads to the accumulation of abnormal white blood cells and impaired production of normal blood cells. AML is the most common acute leukemia in adults, and it appears increasingly with age. Despite overall improvement in the treatment of leukemia in the past few decades, AML still carries a devastating prognosis for elderly patients. Given the advanced age of the AML patients, intensive chemotherapies and hematopoietic stem cell transplantation have increased risk. Thus, new therapies for AML are necessary. A subset of AML cells called stem cells make more malignant cells than other cells, and these cells need to be eradicated to achieve deep therapeutic responses. AML stem cells share some similarities with healthy stem cells that produce normal blood. Thus, identifying ways to distinguish AML stem cells from normal stem cells is important, as damaging the normal stem cells will negatively impact the patient. Our lab focuses on identifying unique features that distinguish AML stem cells from normal blood-forming stem cells. We focus on a process called metabolism, through which cells take up nutrients to make energy. Since cancer cells grow faster than normal cells, we believe that the way cancer cells metabolize nutrients may be different from how normal cells do so. Indeed, we found that AML stem cells heavily rely on a protein called AMPK to metabolize nutrients, while normal blood cells rely less on AMPK and only under specific circumstances. Inhibition of AMPK kills AML stem cells in animal models without harming normal blood-forming stem cells, paving the way to develop new therapies to specifically target AML stem cells. The current project extends our understanding of AML metabolism by investigating whether metabolites control the expression of genes called oncogenes, which are critical for AML development. We are testing the hypothesis that inhibition of AMPK blocks metabolism, which then attenuates the ability of AML stem cells to express oncogenes. The implication of our study is that combining AMPK inhibitors with recently developed targeted cancer drugs that inhibit oncogene expression may have a synergistic effect in suppressing AML. Ultimately, we hope that our research will lead to improved therapies against AML, targeting metabolism to block oncogene expression in AML stem cells.