Targeting the pathogenic 'fire triangle' of inflammation, metabolism and mutations in myeloid leukemogenesis
Eric Pietras
PhDUniversity of Colorado Denver, Anschutz Medical Campus
Project Term: July 1, 2023 - June 30, 2028
My lab is focused on understanding the pathogenic interplay between oncogenic mutations, chronic inflammation and aberrant metabolism as a driver of the evolutionary processes that culminate in lethal myeloid malignancies. We leverage mouse models and human patient samples to establish modalities for targeting this interplay throughout disease pathogenesis. My long-term goal is to improve patient outcomes by establishing therapies that prevent and/or delay evolution to acute leukemia.
Despite decades of intensive effort, blood cancers like acute myelogenous leukemia (AML) remain largely incurable diseases. Outcomes are often poor, and many patients eventually die of this blood cancer. Even recently developed treatment approaches that seek to eradicate the disease-causing stem cells that give rise to AML in the bone marrow carry a high relapse rate. An approach that we and others have pursued in the last few years is to identify ways to prevent and/or delay onset of malignancy by interfering with the evolution of disease at earlier stages. One of the greatest challenges in developing such early interventions has been our lack of knowledge about how the disease process starts. The Pietras Lab is interested in identifying new drugs that can target the abnormal features of stem cells that gain DNA mutations, well before they evolve into cancer. To improve our ability to eradicate these stem cells, we have closely studied the life history of AML from the earliest stages, when blood stem cells acquire their first mutation, through a malignant condition called myelodysplastic syndrome, in which disease-causing MDS stem cells (MDS-SC) often eventually give rise to AML. Our goal has been to find a common thread that links the early and late stages of disease prior to the development of cancer. One common feature at both stages is the presence of a high level of inflammation. Normally, inflammation is beneficial because it activates our immune systems to fight infections. However, experiments we conducted show that high levels of inflammation, which is associated with increased risk of developing AML, can be unhealthy for normal cells. Furthermore, we found that mutant stem cells use inflammation to increase the amount of energy they produce, giving them an even greater ability to take over the bone marrow and cause disease. Based on these new discoveries, we propose to test whether these stem cells may rely upon inflammation to make the high levels of energy they need to grow and expand. If so, we could potentially block inflammation or the altered energy pathways it triggers to reduce the energy these cells can use. We are testing whether this approach can prevent expansion of mutant stem cells or even eradicate them in individuals with MDS. The primary goal of our research proposal is to better understand the interplay between inflammation and metabolism, and to develop strategies for clinical trials aimed at preventing AML development.