Guelph, Canada – A new editorial paper was published in Oncotarget entitled, “Reductive carboxylation of glutamine as a potential target in acute myeloid leukemia.”
In this new editorial, researchers Alessia Roma, Lawrence D. Goodridge and Paul A. Spagnuolo from the University of Guelph discuss acute myeloid leukemia (AML) — an aggressive cancer of the blood and bone marrow defined by poor patient outcomes and sub-optimal therapeutics.
Recent advancements in our understanding of AML biology bring optimism to improving patient outcomes for this devastating disease. For example, the discovery and validation of metabolic vulnerabilities that are distinct to AML open new strategies for novel drug development. In fact, since 2017, a third of newly approved AML therapeutics have targeted metabolic abnormalities. Thus, further identification and elucidation of metabolic vulnerabilities in AML could lead to novel therapies aimed at improving patient outcomes.
Notably the researchers observed that inhibiting complexII (CII) of the electron transport chain (ETC) targeted AML in vivo and in vitro without adversely affecting normal hematopoiesis. CII inhibition resulted in a truncation of the tricarboxylic acid cycle (TCA) that significantly impaired synthesis of key metabolites (e.g., aspartate). Consequently, a reverse TCA cycle, referred to as glutamine-mediated reductive carboxylation, was activated to overcome this truncation. As a result of activation, normal hematopoietic cells maintained anaplerosis while AML cells did not; failure to activate this pathway resulted in selective AML cell death. Similarly, inhibition of glutaminase further sensitized cells to CII inhibition, as glutamine was prevented from entering the TCA cycle. These findings raise more questions worthy of future investigation. Specifically, does inhibiting CII offer any advantage over other ETC targets, can reductive carboxylation be directly targeted in AML, and are these targets (e.g., CII or reductive carboxylation) specific to an AML subtype?
“One approach is to weaken tumor cell survival mechanisms. In this regard, exploring reductive carboxylation as a possible drug target could provide new avenues for optimizing existing treatments aimed at improving AML patient outcomes”, says Professor Paul A. Spagnuolo co-first author of the study.
Contact
Paul A. Spagnuolo Ph.D
Email [email protected]