Feasibility and Safety of Targeting Mitochondria Function and Metabolism in Acute Myeloid Leukemia.

Abstract

Purpose of review: Acute myeloid leukemia (AML) is a clonal blood neoplasm with dismal prognosis. Despite the introduction of many novel targeted agents, cytotoxic chemotherapy has remained the standard of care for AML. Differences in mitochondrial metabolism between normal and leukemic cells can be targeted by novel AML therapies, but these agents require a comprehensive efficacy and cytotoxicity evaluation.

Recent findings: Metabolic alterations in AML blasts increase their sensitivity to therapies targeting mitochondrial metabolism. Targeting altered mitochondrial metabolism, that is crucial for leukemia cell growth and survival, could be a breakthrough in AML treatment. Therefore, BH3 family proteins, mitochondrial complexes, the tricarboxylic acid cycle, and amino acid (AA) and fatty acid metabolism are common treatment targets in AML. Although many drugs targeting these vulnerabilities showed acceptable safety profiles and promising efficacy in preclinical studies, clinical trials often do not confirm these results limited by narrow therapeutic window. The most effective regimens are based on drug combinations with synergistic or additive activity.

Summary: In this review, we present an overview of the most recent studies targeting mitochondrial metabolism in AML. We highlight that targeting of the specific energy metabolism dependencies of AML blasts provides an opportunity to achieve long-term responses with a reasonable safety profile. We emphasize that currently used drugs and their combinations display dose-limiting toxicities or are not efficient enough to completely eradicate leukemic stem cells. Thus, further studies of complex metabolic rewiring of leukemia cells before and after combinatorial therapies are warranted.