Dr. Courtney Jones: 2021 CDP Achievement Award Winner

Dr. Jones was awarded the CDP Special Fellow Award in 2019 for her project titled Targeting Metabolic Vulnerabilities of Relapsed Leukemia Stem Cells:

"This project aims to improve acute myeloid leukemia (AML) patient outcomes by combating leukemia stem cells (LSC) in relapsed AML patients by targeting nicotinamide – a molecule that we discovered to be an energy source of LSCs in relapsed AML patients. In the United States, approximately 10,000 people die every year from AML. AML occurs because DNA from normal blood cells becomes damaged. This damage changes a normal blood stem cell into a LSC. LSCs are the reservoir of cells that give rise to all other leukemia cells, called blasts, which manifest as symptomatic disease. Importantly, many studies have shown that LSCs are different from leukemic blasts. For instance, LSCs do not respond to current AML therapy while blasts do. This fundamental difference between LSCs and blasts is observed in the clinic. While many AML patients initially respond to therapy, LSCs cause a significant portion of AML patients to relapse. Disease relapse is the major cause of death for AML patients. Despite the limitations with current AML treatments, therapies for eliminating the LSCs in relapsed AML have not been widely explored.

LSCs from patients who have relapsed are different from LSCs from newly diagnosed patients; therefore, we need a strategy to specifically eliminate LSCs in relapsed patients. We recently showed that LSCs from newly diagnosed patients can be targeted by inhibiting processes that generate energy for the LSCs. We hypothesized that relapsed LSCs have different metabolic requirements that contribute to therapy resistance, which could be targeted to specifically eliminate these cells. Therefore, we studied the differences in metabolism between LSCs from newly-diagnosed and relapsed AML patients and identified that relapsed LSCs have a higher level of a molecule called nicotinamide which is known to be involved in cellular processes involved in energy production. Our preliminary data shows that inhibiting nicotinamide function selectively kills relapsed LSCs by decreasing energy production specifically in these relapsed LSCs but not in LSCs from patients never treated with prior therapy. In our current research, we will expand on our preliminary data to determine if targeting nicotinamide function is advantageous for the majority of relapsed AML patients. In addition, we will deepen our understanding of why relapsed LSCs rely on nicotinamide for survival and energy production using a variety of metabolic and genetic experimental approaches. These studies will provide the basis for novel strategies to treat relapsed AML patients, who desperately need better treatment options.

Funding from the LLS during the award period (2019-2020) allowed her to advance research across multiple research topics. The goal of the work proposed in her CDP Special Fellow award was to characterize and target metabolic properties that are specific to leukemia stem cells (LSCs) in relapse acute myeloid leukemia (AML) patients. She pursued this line of research for two main reasons:

1. her team and others have shown that LSCs have specific metabolic properties that can be targeted to eradicate LSCs, and 
2. relapsed AML patients have a significantly worse overall survival when treated with the now approved regimen of venetoclax with azacitidine, which targets LSC metabolism, compared to newly diagnosed AML patients

Together, these data led to the hypothesis that relapsed LSCs have different metabolic properties that may be therapeutically targetable. To test this hypothesis, her team performed mass spectrometry-based metabolomics analysis on LSCs enriched from primary human diagnosis and relapsed AML patients. These experiments led to two important observations:

1. Both nicotinamide and fatty acid metabolism were elevated in relapsed LSCs compared to diagnosis LSCs.
2. Elevating either nicotinamide or fatty acid metabolism results in resistance to venetoclax with azacitidine in LSCs. Importantly, inhibiting nicotinamide and fatty acid metabolism killed relapsed LSCs alone or sensitized them to venetoclax with azacitidine.

This work resulted in her being named a New York Academy Rising Star in Tumor Metabolism research in April 2021.

All first author publications and presentations during the award period:

• Jones et al. Blood. 2019.
• Jones et al. Cell Stem Cell. 2020
• Stevens*, Jones*, Pollyea* et al. Nature Cancer. 2020
• Jones et al. ASH Annual Meeting (2019)