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Principal Investigator: Craig T. Jordan
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $884,768
Funding agency: National Cancer Institute
Summary
This proposal is focused on the development of improved therapies for acute myeloid leukemia (AML).
The central premise of our all our work is that AML is driven by a biologically distinct leukemia stem cell
(LSC) population. While the conceptual importance of targeting leukemic disease at its root is clear,
studies in recent years have demonstrated that the inherent intra-patient heterogeneity of LSC
populations makes complete eradication a very challenging objective for most patients. Our studies
have therefore attempted to identify common foundational properties of primary human LSCs that can
employed in the development of therapeutic strategies in the hope that intrinsic heterogeneity can be
overcome. Of particular interest, we have described distinct metabolic properties in LSCs, that provide
new opportunities for intervention. Specifically, inhibition of BCL2 acts to inhibit oxidative
phosphorylation in LSCs, resulting in selective eradication of the LSC population. Recent translation
of this observation to clinical studies has demonstrated strong efficacy for newly diagnosed AML
patients, and appears to be on the verge of altering the current standard of care. Despite these exciting
advances though, relapse remains common and further elucidation of LSC properties is essential. To
this end, we have recently begun to describe the mechanisms that drive relapse of AML patients
following treatment with a BCL2 inhibitor. These studies have identified entirely unexpected and new
aspects of LSC biology that have important ramifications for our basic understanding of AML, as well
as the design of improved therapeutic regimens. Specifically, we have demonstrated that at least two
distinct LSC populations can co-exist in the same patient. The genetic, epigenetic, and metabolic
properties of co-resident LSC subpopulations can vary, giving rise to differing levels of drug
responsiveness. The focus of our studies going forward will be to understand and exploit these findings
towards the goal of improved outcomes for AML patients.
Terms: <AML - Acute Myeloid Leukemia><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Applications Grants><B cell lymphoma 2><B-Cell CLL/Lymphoma 2 Gene><B-cell lymphoma/leukemia-2><BCL2><BCL2 gene><Bcl-2><Clinical Research><Clinical Study><Development><Disease><Disorder><Drugs><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Genetic><Goals><Grant Proposals><Heterogeneity><Human><Intervention><Intervention Strategies><Leukemic progenitor and stem cell><Medication><Metabolic><Modern Man><Newly Diagnosed><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Patients><Pharmaceutical Preparations><Property><Regimen><Relapse><Therapeutic><Translations><Work><acute granulocytic leukemia><acute myeloid leukemia><bcl-2 Genes><ced9 homolog><design><designing><developmental><drug/agent><epigenetically><improved><improved outcome><inhibitor><interest><interventional strategy><leukemia><leukemic progenitor><leukemic stem cell><progenitor biology><progenitor cell biology><progenitor cell population><progenitor population><standard of care><stem and progenitor biology><stem and progenitor cell population><stem cell biology><stem cell population><therapeutic agent development><therapeutic development><therapeutic target><translation>